SAGE-Hindawi Access to Research
Journal of Nucleic Acids
Volume 2010, Article ID 592980, 32 pages
MolecularMechanismsof Ultraviolet Radiation-InducedDNA
Damage and Repair
RajeshP.Rastogi,1Richa,1Ashok Kumar,2Madhu B.Tyagi,3andRajeshwarP. Sinha1
1Laboratory of Photobiology and Molecular Microbiology, Centre of Advanced Study in Botany, Banaras Hindu University,
Varanasi 221005, India
2School of Biotechnology, Banaras Hindu University, Varanasi 221005, India
3Mahila Maha Vidyalaya, Banaras Hindu University, Varanasi 221005, India
Correspondence should be addressed to Rajeshwar P. Sinha, email@example.com
Received 11 June 2010; Revised 15 August 2010; Accepted 28 September 2010
Academic Editor: Shigenori Iwai
Copyright © 2010 Rajesh P. Rastogi et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
DNA is one of the prime molecules, and its stability is of utmost importance for proper functioning and existence of all living
systems. Genotoxic chemicals and radiations exert adverse effects on genome stability. Ultraviolet radiation (UVR) (mainly UV-B:
280–315nm) is one of the powerful agents that can alter the normal state of life by inducing a variety of mutagenic and cytotoxic
DNA lesions such as cyclobutane-pyrimidine dimers (CPDs), 6-4 photoproducts (6-4PPs), and their Dewar valence isomers as
well as DNA strand breaks by interfering the genome integrity. To counteract these lesions, organisms have developed a number
of highly conserved repair mechanisms such as photoreactivation, base excision repair (BER), nucleotide excision repair (NER),
and mismatch repair (MMR). Additionally, double-strand break repair (by homologous recombination and nonhomologous end
joining), SOS response, cell-cycle checkpoints, and programmed cell death (apoptosis) are also operative in various organisms
with the expense of specific gene products. This review deals with UV-induced alterations in DNA and its maintenance by various
The stratospheric ozone layer is continuously depleting
due to the release of atmospheric pollutants such as chlo-
rofluorocarbons (CFCs), chlorocarbons (CCs), and organo-
bromides (OBs). Consequently there is an increase in the
incidence of UV radiation (UVR) on the Earth’s surface
 which is one of the most effective and carcinogenic
exogenous agents that can interact with DNA and alter the
genome integrity and may affect the normal life processes
of all organisms ranging from prokaryotes to mammals [2–
10]. However, wide variations in tolerance to UV-B among
predicted to continue throughout most of this century .
In all the groups of UVR (i.e., UV-A: 315–400nm; UV-
B: 280–315nm; UV-C: <280nm) UV-B radiation produces
adverse effects on diverse habitats, even though most of the
extraterrestrial UV-B is absorbed by the stratospheric ozone
. UV-A radiation has a poor efficiency in inducing DNA
damage, because it is not absorbed by native DNA. UV-
A and visible light energy (up to 670–700nm) are able to
generate singlet oxygen (1O2) that can damage DNA via
indirect photosensitizing reactions . UV-C radiation is
quantitatively absorbed by oxygen and ozone in the Earth’s
atmosphere, hence does not show much harmful effects on
biota. Solar UV radiation is responsible for a wide range
of biological effects including alteration in the structure
of protein, DNA, and many other biologically important
molecules, chronic depression of key physiological processes,
and acute physiological stress leading to either reduction in
growth and cell division, pigment bleaching, N2 fixation,
energy production, or photoinhibition of photosynthesis in
several organisms [3, 9, 10]. It has been documented that
UV-B severely affects survival, fecundity, and sex-ratio in
several intertidal copepods . One of the most prominent
2Journal of Nucleic Acids
DNA damaging agents
SSBDSBCPD AP-SiteDeaminationMispaired base
Failure of repair
Adenine Guanine Cytosine Thymine Uracil
Figure 1: DNA damage and maintenance. Genomic lesions produced by various DNA damaging agents trigger several specific repair
machinery to conserve the genomic integrity. In case of severe damage and/or failure of repair mechanisms, cells undergo apoptosis or
induce a complex series of phenotypic changes, that is, SOS response. Sometimes the potentiality of lesions in the genome is mitigated by
a phenomenon known as damage tolerance, during which DNA lesions are recognized by certain repair machinery, allowing the cells to
undergo normal replication and gene expression. The cellular response to DNA damage may activate cell-cycle checkpoint by means of a
network of signaling pathway that gives the cell extra time to repair the genomic lesions or may induce cell suicide response/programmed
cell death (PCD).
targets of solar UV-radiation is cellular DNA, which absorbs
UV-B radiation and causes adverse effects on living systems
such as bacteria [15, 16], cyanobacteria , phytoplankton
, macroalgae , plants , animals, and humans
Although UV-B radiation has less than 1% of total
solar energy, it is a highly active component of the solar
radiation that brings about chemical modification in DNA
and changes its molecular structure by the formation of
dimers. Certain UV-absorbing pigments are produced by
a number of organisms as a first line of defense; how-
ever, they are unable to avoid UV-radiation completely
from reaching DNA in superficial tissue [28–32]. Certain
enzymes, such as superoxide dismutase (SOD), catalase
(CAT), peroxidase (POD), and scavengers such as vitamin
C, B, and E, cysteine, and glutathione play an additional
role in defense against UV radiation . However, as a
second line of defense several organisms have developed a
number of specific and highly conserved repair mechanisms
such as photoreactivation, excision repair, mismatch repair
(MMR), double strand break (DSB) repair and certain other
our soul) response, checkpoint activation, and programmed
cell death (PCD) or apoptosis (Figure 1) that efficiently
remove DNA lesions ensuring the genomic integrity .
Plants are unique in the obligatory nature of their exposure
to UVR; it is also conceivable that they may also have evolved
certain efficient repair mechanisms for the elimination of
UV-induced DNA damage. However, a number of questions
concerning the basic phenomena of the DNA repair in plants
remain to be elucidated. In the following, we discuss the
molecular mechanisms of UV-induced DNA damage and
repair mechanism (s) operative in various organisms.
2.UV-Induced DNA Damage
Induction of DNA damage by solar UVR is a key event
that drastically influences the normal life processes of all
organisms. A number of endogenous factors such as free
radicals  generated during metabolic processes as well
as exogenous factors such as UV or ionizing radiations
 are known to interfere with genome integrity. DNA
damage results in (i) misincorporation of bases during
replication process, (ii) hydrolytic damage, which results in
deamination of bases, depurination, and depyrimidination
, (iii) oxidative damage, caused by direct interaction
of ionizing radiations (IR) with the DNA molecules, as
well as mediated by UV radiation-induced free radicals or
reactive oxygen species [37, 38], and (iv) alkylating agents
that may result in modified bases [36, 39]. The hydrolytic
deamination (loss of an amino group) can directly convert
Journal of Nucleic Acids3
Figure 2: Structures of DNA duplexes showing the presence of lesions (in green) such as CPD (a), 6-4PP (b), and 6-4 Dewar dimer (c).
Hydrogen atoms are not shown, prepared from PDB entries 1TTD , 1CFL , and 1QKG  using PyMol. (version 1.1r1) .
one base to another; for example, deamination of cytosine
results in uracil and at much lower frequency adenine to
hypoxanthine. In depurination/depyrimidination, there are
complete removals of purine/pyrimidine bases, leaving the
deoxyribose sugar depurinated/depyrimidinated, that may
cause breakage in the DNA backbone. The exposure of UVR,
IR, and certain genotoxic chemicals may result in single as
well as double DNA strand breaks. Among different types
of damages, DNA double strand breaks (DSBs) are the most
deleterious, since they affect both strands of DNA and can
lead to the loss of genetic material. At high concentrations
oxygen-free radicals or, more frequently, reactive oxygen
species (ROS) can induce damage to cell structure, lipids,
proteins as well as DNA and results in oxidative stress which
has been implicated in a number of human diseases .
The hydroxyl radicals (OH◦) can damage all components of
the deoxyribose backbone, inhibiting the normal functions
of the cell [37, 38].
UV-B radiation is one of the most important energetic solar
components that may lead to the formation of three major
classes of DNA lesions, such as cyclobutane pyrimidine
dimers (CPDs), pyrimidine 6-4 pyrimidone photoproducts
(6-4PPs), and their Dewar isomers (Figure 2) [5, 22, 23, 41–
43]. CPDs correspond to the formation of a four-member
whereas 6-4PPs are formed by a noncyclic bond between C6
(of the 5?-end) and C4 (of the 3?-end) of the involved pyrim-
idines via spontaneous rearrangement of the oxetane (when
the 3?-end is thymine) (Figure 3(a)) or azetidine (when the
4PPs are eagerly converted into their Dewar valence isomers
upon exposure to UV-B or UV-A radiation that may further
undergo reversion to the 6-4PPs upon exposure to short-
wavelength UV radiation . Two adjacent cytosines are
. It has been found that T-T and T-C sequences are
more photoreactive than C-T and C-C sequences . The
diastereoisomers of pyrimidine dimers (Figure 4) can be
observed in free solution that differ in the orientation of
the two pyrimidine rings relative to the cyclobutane ring,
and on the relative orientations of the C5–C6 bonds in each
photoproducts are cis-syn-configured CPD lesions, while
trans-syn-configured CPD lesions are formed in much less
quantity . In double stranded B-DNA, where the dimer
entails two adjoining pyrimidine bases on the same DNA
strand, only the syn isomers can be generated, whereas the
cis isomer is preferred over the trans isomer to a great extent
. The incidence of trans-syn isomer in single-stranded or
denatured DNA is more common because of the increased
flexibility of the DNA backbone. A few CPD lesions (i.e., cis-
syn or trans-anti isomers) can also be detected in aqueous
4 Journal of Nucleic Acids
Figure 3: Pathway of UVR-induced T-T (a) and T-C (b) CPD, 6-4PPs, and their Dewar isomers.
solutions by UV-C irradiation . The formation of “spore
photoproduct” has been detected in UV-irradiated bacterial
spores by the addition of methyl group of one thymine
residue to the C5 position of an adjacent thymine. In most
cellular environments, there is no much significance of this
photoproduct, since it requires anhydrous conditions for its
The base damage by UVR is determined by the flexibility
of the DNA strand as well as nature and position of the
base. CPDs are formed at higher quantity by cycloaddition
reaction between two pyrimidine bases  in single-
stranded DNA (ssDNA) and at the flexible ends of poly
(dA)-(dT) tracts, but not at their rigid centre [50, 51].
Bending of DNA towards the minor groove reduces CPDs
formation . One of the transcription factors, TATA-box
binding protein (TBP), promotes the selective formation
of 6-4PPs in the TATA-box, where the DNA is bent, but
CPDs are formed preferentially at the edge of the TATA
box and outside where the DNA is not bent . The
amounts of CPDs and 6-4PPs are about 75 and 25%,
; however, the ratio between the yield of CPDs and 6-
4PPs mainly depends upon the two adjacent bases involved
in the formation of dimers . Thus the heterogeneous
distribution of the UV-induced photolesions in the DNA
as the chromatin modulation through the binding of specific
protein . Mapping of CPDs in the nucleosome core
Journal of Nucleic Acids5
Figure 4: Possible diastereoisomers of pyrimidine T <> T dimer.
Figure 5: Formation of cytosine photohydrate (6-hydroxy-5,6-
dihydrocytosine) as a result of photohydration reaction.
regions of UV-treated chromatin has revealed the formation
of CPDs with an average distance of 10.3 bases, away from
the surfaceof histones . The formation of photoproducts
is not restricted to cells exposed to UV-B or UV-B + UV-A
radiations; UV-A-induced formation of CPDs has also been
observed in bacteria as well as in eukaryotic cells and whole
skin [57–59]. Recent studies on the effects of UV-A radiation
on rodent and human skin cells have revealed that CPDs
are in larger yields than 8-oxo-7,8-dihydroguanine (the most
frequent UVA-induced DNA lesion) and DNA strand breaks
[48, 60]. The occurrence of 5-methylcytosine-containing
photoproducts in UV-irradiated DNA is still controversial.
However, Su et al.  have reported a new photoproduct
of 5-Methylcytosine and Adenine characterized by high-
An additional photochemical characteristic for cytosine
is the formation of monomeric pyrimidine photoproduct
“cytosine photohydrate” (6-hydroxy-5,6-dihydrocytosine) as
a result of photohydration reaction (Figure 5) . There
is little information concerning the formation of cytosine
hydrates in UV-irradiated DNA due to instability of the
resulting photoproduct . The oxidation product of
pyrimidine bases such as pyrimidine glycols is also formed
by means of hydration reaction .
Adenine dimer Porschke photoproduct T-A photoadduct
porschke photoproduct and thymine-adenine photoadduct.
Although dipyrimidine photoproducts are the preferential
radiation-induced modifications of DNA purine bases has
also been recognized . These comprise the photoprod-
uctsthatinvolve, atleast, one adenine residue that undergoes
photocycloaddition reactions with contiguous adenine or
thymine (Figure 6) upon exposure to UV-B radiation [65,
66]. The extent of adenine-containing photoproduct (A-T)
is very low (1 × 10−5in native DNA) but these lesions
may contribute to the biological effects of UV radiation in
view of the fact that the A-T adduct has been shown to
be mutagenic [67, 68]. Photodimerization of adenine (A)
involves the cycloaddition of N7-C8 double bond of the
5?-A across the C6 and C5 positions of the 3?-A [65, 69]
and generates a very unstable azetidine intermediate. This
intermediate photoproduct undergoes competing reaction
pathways to form two distinct adenine photoproducts
such as adenine dimer (A=A) and P¨ orschke photoproduct
(Figure 6) . Conversion of both these photoproducts
into 4,6-diamino-5-guanidinopyrimidine (DGPY) and 8-
(5-aminoimidazol-4-yl)adenine (8-AIA), respectively, can
be detected from individual acid hydrolysates of UV-
irradiated polynucleotides and DNA . It has been
found that complexing of UV-irradiated poly(dA)-poly(dT)
effectively reduces the formation of A=A photoproduct .
Moreover, photoreactivity of adjoining adenine bases in
DNA is strongly suppressed by the complementary base
pairing [50, 72]. UV-induced ROS acts as a powerful
oxidant that may cause oxidative DNA damage. A number
of oxidation products of purine bases such as 8-oxo-
7,8-dihydroguanyl (8-oxoGua), 8-oxo-Ade, 2,6-diamino-
4-hydroxy-5-formamidoguanine (FapyGua), FapyAde, and
oxazolone have been reported to form upon exposure of
DNA to UV radiation [44, 73, 74].
Overall, it has been concluded that UV-induced DNA
lesions such as CPDs, 6-4PPs, abasic site, strand breaks, and
oxidative product are the predominant and most persistent
tions in the DNA molecule, thereby affecting the important
cellular processes such as DNA replication and transcription,
compromising cellular viability and functional integrity and
ultimately leading to mutagenesis, tumorigenesis, and cell
death [30, 36].
6Journal of Nucleic Acids
Figure 7: Cis-syn CPD showing the right-handed or left-handed
twist in DNA duplex. Dotted arrows elucidate the strongest nuclear
from Lukin and de los Santos ).
5.DifferentialEffects of CPDsand 6-4PPs on
UV-induced DNA lesions such as CPDs and 6-4PPs show
differential effects on DNA conformation, impairing their
regulatory functions and other dynamic processes [24, 26,
75, 76]. Nuclear Magnetic Resonance (NMR) spectroscopy
has presented new insights on UV radiation-induced nucleic
acid conformation. It has been well established that the
comparative orientation of damaged residues is unusual
from that observed in unmodified DNA duplexes .
Nuclear overhauser enhancement (NOE) study of interac-
tions among the photoadduct H6 and methyl (CH3) groups
has established that the cis-syn CPD changes the cyclobutane
conformation from a left-handed twist (observed in the
isolated dimer) to a right-handed twist in DNA duplex 
(Figure 7). Assessment of the chemical shift data suggests
that the DNA helix is disturbed more along the 3?- and
5?-side of the cis-syn and trans-syn dimer, respectively. It
was revealed that the presence of trans-syn CPD causes
distortion to a great extent than the cis-syn product by
means of a kink or dislocation at the 5?-side of the dimer
in double-stranded DNA . NMR and X-ray diffraction
studies of the ultraviolet photoproduct, cis-syn CPD, with
the S-cyanoethyl phosphotriester have revealed that the two
pyrimidine bases are rotated by −29◦base twist, contrasting
to the right-handed 36◦value observed in B-form DNA
[78, 79]. Moreover, in contrast to the cis-syn CPD, the duplex
spectra of the trans-syn lesion illustrated no abnormally
shifted31P or imino proton signal, signifying the absence
of major distortions in the conformation of the sugar-
phosphate backbone . The thymine (T) residues of the
CPD form stable wobble pairs with the opposite guanine
(G) residues. The T6-G15 wobble pair of the CPD formed
hydrogen bonds between the T6-imino and G15-O6 and
between the G15-imino and T6-O2. The two T (T5, T6)
residues of the CPD in the CPD/GG duplex form wobble
base pairs with the opposite G residues, similar to the T6-
G15 base pair in the CPD/GA duplex . It has been
reported that the preexisting CPDs in the DNA molecule
can influence its rotational setting on the histone surface
during nucleosome formation . Recently, Rumora et al.
 have examined the thymine dimer-induced structural
changes to the DNA duplex with several small, base-selective
reactive chemical probes. The formation of 6-4PPs and their
of DNA duplex. The one- and two-dimensional NMR data
on the (6-4)-adduct-containing DNA duplex decamer was
analyzed in H2O and D2O solutions to elicit the base pairing
and unusual conformation in the vicinity of the lesion [76,
83, 84]. The distortion of the double helix caused by the 6-
4PP is much greater than that of the CPD .
The main conformational perturbations caused by the
(6-4) adduct and Dewar product are concerned with their
effects on global DNA curvature. Both duplex decamers are
the 5,6-dihydro-5-hydroxythymine base is the most per-
turbed part of the 6-4 Dewar lesion. Even though there are
no hydrogen bonds between 5,6-dihydro-5-hydroxythymine
and its partner adenine residue, this lesion produces minor
distortions in comparison to the 6-4PP. In general helical
is 44◦and 21◦, respectively . All the supplementary
imino proton resonances from the flanking base pairs were
observed in the hydrogen-bonded region, which indicate
that the structure of the (6-4) adduct inside the duplex
shows a distinctive base orientation due to (6-4) covalent
linkage which makes a normal Watson-Crick-type hydrogen
bonding unfavorable at the 3?-side of the lesion site with an
empty space between the 3?-thymine (T6) and its opposite
retains a hydrogen-bonded imino proton at the 5?-side (T5)
of the (6-4) lesion, the T5 imino proton of the Dewar lesion
is not hydrogen-bonded. The NMR characterization of a
6-4PP dimer containing duplex showed that the 5?-residue
of the lesion remains essentially unperturbed. However, the
5?-pyrimidine residue looses aromaticity and acquires an
additional hydrophilic group [75, 83]. The glycosyl bond
torsion angle at the T5 residue of the (6-4) lesion and the
respectively, and thus both the lesions exhibit considerable
differential effects on DNA backbone conformation. It has
been observed that the large structural distortion induced by
the (6-4) lesion may ensure a favorable recognition by the
repair enzyme, which may possibly elucidate the correlation
with the elevated repair rate of the T-T (6-4) adduct than of
the T-T Dewar product and the T-T cis-syn dimer .
6.UV-Induced DNA Double Strand Breaks
The generation of DNA double strand breaks (DSBs) in
UV-irradiated cells, specifically in replicating DNA, has
been known for a long time . DNA strand breaks
are observed extensively in cells under UV-B irradiation
[87, 88]. UV-B-induced ROS  as well as DNA lesions
Journal of Nucleic Acids7
Collapse of replication forks
Induction of DSBs
UVR, IR, ROS
Figure 8: Schematic representation showing different pathways of DSBs.
(CPDs and 6-4PPs) may cause primary as well as secondary
breaks, respectively. These lesions are commonly associated
with transcription/replication blockage that may lead to
production of DNA double-strand breaks (DSBs) at the sites
of collapsed replication forks of CPDs-containing DNA [90,
91] (Figure 8). Dunkern and Kaina  also observed UV-
C-induced DNA DSBs, arising from replication of damaged
DNA. A significantly low amount of DSBs was found in the
cell where replication was inhibited. It was assumed that
initial photoproducts are converted into DSBs during DNA
replication, due to not a distinct process, that is, “collapse
of replication forks” . After labeling of replicating DNA
of UV-irradiated SV40-transformed human cell lines with
radioactive precursors, an increased number of DSBs was
observed in NER deficient cells in comparison to NER
proficient cells. These results further support the view that
DSBs are produced during the replication of unrepaired UV-
induced DNA lesions . DSBs can be formed in response
to the repair of single strand breaks (SSBs) passing through
base excision repair (BER) [94, 95]. Overall, it seems that
UV radiation does not directly produce DNA DSBs but
rather produces pyrimidine dimers and other photoprod-
ucts leading to replication arrest and DSBs. UV-induced
replication arrest in the xeroderma pigmentosum variant
(XPV) followed by the accumulation of Mre11/Rad50/Nbs1
complex and phosphorylated histone H2AX (γ-H2AX) in
large nuclear foci at sites of stalled replication forks also
suggests that UV damage leads to the formation of DSBs
during the course of replication arrest [90, 95].
A number of pathways have been considered for the
formation of DSBs at a stalled replication fork. It was shown
that when the DNA replication machinery encounters a
replication-blocking lesion, DNA polymerase (DP) enzyme
is stalled at the blocked site resulting in the formation of a Y-
endonuclease, that successively makes a nick in the template
strand resulting in the induction of a DSB close to the
replication-blocking lesion . Furthermore, replication
stresses may trap topoisomerase I (Top1) cleavage complexes
leading to generation of DSBs by preventing Top1-mediated
DNA religation . Free radicals may also cause DSBs
 by preventing the topoisomerase II (Top2)-mediated
DNA religation [144, 147]. Recently, Harper et al. 
have shown that radiation-induced SSBs and non-DSB DNA
damage contribute to the formation of replication-induced
DSBs. In spite of the above possible facts regarding the
formation of DSBs, more experimental evidences are still
7.Detectionof DNA Damage
Several workers have attempted to detect different types
of DNA lesions and presently a number of detection
strategies are widely used (Table 1). An alkaline gel method
for quantitating single-strand breaks (SSBs) in nanogram
et al. . Mitchell et al.  have developed a method for
substances followed by agarose gel electrophoresis and den-
sitometric analysis and finally digesting with endo. III and
endo.V before analyzing on sequencing gels. UV-B induced
DNA damage in mammalian genome was reported by Wang
et al.  using the PCR-based short interspersed DNA
element- (SINE-) mediated detection method. For analyzing
the 6-4PPs, terminal transferase-dependent PCR (TD-PCR)
of genomic DNA of cyanobacterium Anabaena strain BT2
was documented by Kumar et al.  using the PCR-
based assays such as random amplified polymorphic DNA
(RAPD) and rDNA amplification. Similarly, UV-B-induced
DNA damage was also detected in Anabaena variabilis
PCC 7937 and Rivularia sp. HKAR-4 by PCR (data not
published). The formation of thymine dimer (T∧T) within
8Journal of Nucleic Acids
Table 1: Various strategies for the detection of damaged DNA.
DNA damage detection strategies
PCR based assay (TDPCR, LMPCR, ICPCR,
Types of lesions detected
Decrease in DNA template activity, T <> T CPDs, 6-4PPs
Commet assay (Single-cell gel Electrophoresis) Oxidative DNA damage and single/double strand break
Halo assay/AHA/FHAChromatin fragility/single strand breaks at the single cell level
TUNEL assay Single/double strand breaks, apoptosis
Oxidative DNA damage; CPDs, 6-4PPs and their related Dewar
valence isomers; 5-hydroxy-2-deoxyuridine,8-oxo-7,8-dihydro-
2-Deoxyadenosine; 5-Methylcytosine and
[48, 54, 61, 106]
FISH Chromosomes with numerical aberrations
Chromosomal aberrations, sister chromatid exchange, chemical
adducts to DNA and DNA strand breakage
Chromatin condensation, DNA fragmentation,
Annexin V labeling
Immuno-dot-blot assay CPDs, 6-4PPs and their Dewar valence isomers
[17, 59, 112, 113]
RIA CPDs and 6-4PPs
Strand break, modified bases, abasic sites, DNA-protein
crosslinks and other oxidative DNA damage.
FADUSingle/double strand breaks and alkali-labile sites
NMR spectroscopyLesions induced distortions of DNA duplex
PCR: polymerase chain reaction; TDPCR: terminal transferasedependent PCR; LMPCR: ligation-mediated PCR; ICPCR: immuno-coupled PCR; SINE:
short interspersed DNA element; AHA: alkaline-halo assay; FHA: fast halo assay; TUNEL: terminal deoxyribonucleotidyl transferase mediated deoxyuridine
triphosphate nick end labeling; HPLC-MS/MS: high-performance liquid chromatography coupled to tandem mass spectrometry; FISH: fluorescence in
situ hybridization; FCM: flow cytometry; RIA: radio immunoassay; ELISA: enzyme-linked immunosorbent assay; GC-MS: gas chromatography-mass
spectrometry; NMR: nuclear magnetic resonance spectroscopy.
human genomic DNA has been detected by immunocoupled
PCR (IC-PCR) . DNA damage such as SSBs, DSBs,
and oxidative DNA damage caused by UVR, ultrasound
electromagnetic frequency radiation, and so forth may be
detected by comet assay . Recently, a modified version
of comet assay (apo/necro-comet assay) has been developed
that differentiates viable, apoptotic, and necrotic cells and
also correlates the DNA fragmentation pattern . Both
single and DSBs as well as apoptosis can also be detected by
TUNEL assay [104, 105]. However, it has been experienced
that TUNEL assay is not able to distinguish various types
of cell death; hence, an alternate method based on flow
cytometry (FCM) has been developed for the detection of
apoptosis . Recently, apoptosis in tumor cells caused
by X-rays has been analyzed using125−I-labeled annexin
V . FCM assay is useful in detecting chromosomal
aberrations, sister chromatid exchange, chemical adducts to
DNA, and DNA strand breakage . Alkaline unwinding
FCM (AU-FCM) may be used to detect nucleotide excision
repair (NER) . The changes in DNA organization
in the individual cells can be determined by halo assay
. SSBs at the single cell level can be assessed by
alkaline-halo assay (AHA), where cells are embedded in
melted agarose and spread on the microscope slide and
then incubated in a high-salt alkaline lysis solution followed
by another incubation in a hypotonic alkaline solution
and, finally, stained with ethidium bromide (EtBr). Under
these conditions, single-stranded DNA fragments diffuse
radically from the nuclear cage . DNA strand breaks
(SSBs, DSBs, and alkali-labile sites) induced by genotoxic
agent such as UVR can also be detected by fluorometric
analysis of DNA unwinding (FADU) assay, which was
first reported by Birnboim and Jevcak  to detect X-
ray-induced DNA damage in mammalian cells. Numerical
aberrations in chromosome can be detected efficiently by
fluorescence in situ hybridization (FISH) method .
UV-induced photoproducts in various organisms such as
mammals, cyanobacteria, phytoplankton, macroalgae, and
liverwort [17, 59, 112, 113]. This technique is based on use
of thymine-dimer specific antibodies followed by blotting
and chemiluminescence method. Another detection strategy
includes radio-immunoassay (RIA)whichis used toestimate
CPDs and 6-4PPs . The very low amount of CPDs
caused by UVR in bacterioplankton and marine viruses may
be detected very efficiently using RIA method . Kara et
al.  have studied the electrochemical detection of DNA
damage by direct and indirect irradiation with radioactive
technetium (TC-99m) and iodine (I-131). Certain pho-
toproducts such as 5-Methylcytosine and adenine can be
detected by high-performance liquid chromatography and
mass spectrometry . Recently, Kumari et al.  have
made an attempt to dissect various strategies for detection of
DNA lesions produced by a number of genotoxic agents.
Journal of Nucleic Acids9
Table 2: Photolyase enzymes in four different kingdoms.
KingdomOrganism CPD Photolyase
Synechocystis sp. PCC 6803
Fowl pox virus (FPV)
Melanoplus sanguinipes entomopox virus
Chrysodeixis chalcites nucleopolyhedrovirus
The idea about the ability of living beings to overcome the
lethal effects of UV-radiation emerged as early as the mid
1930s , but the existence of repair mechanisms was
The determination of a particular repair pathway within the
cell mainly depends on the types and location of lesions in
the genome . The biochemical and molecular studies
on repair pathways have been extensively investigated in
some model organisms such as E. coli, S. cerevisiae, and
human, where specialized repair proteins scan the genome
continuously and encounter the DNA lesions by triggering
excision repair (BER and NER), mismatch repair (MMR),
and some specialized forms of repair system such as SOS
response, damage tolerance, and apoptosis.
The process of photoreactivation is executed by means of
a photoreactivating enzyme known as “photolyase”, which
is well conserved and found throughout the three domains
of life (Table 2). The enzyme binds specifically to the CPDs
(CPD photolyase) or 6-4PPs (6-4 photolyase) and directly
monomerizes the cyclobutane ring of the pyr <> pyr, using
the energy of visible/blue-light and protects the genome
from deleterious effects of UVR [157, 158]. The absorption
of every blue-light photon may split approximately one
dimer . CPD photolyases have been reported in diverse
groups such as archaea, bacteria, fungi, virus, plants, inverte-
brates, and many vertebrates including aplacental mammals
(Table 2). On the other hand, 6-4 photolyases have been
identified in certain organisms like Drosophila, silkworm,
Xenopus laevis, and rattle snakes . Photolyases seem to be
10Journal of Nucleic Acids
T > T
Formation of pyrimidine
dimer in UV-exposed DNA
Restoration of normal base pair
T > T
Figure 9: Photoreactivation: incidence of ultraviolet radiation (UVR) results in pyrimidine lesion (thymine dimer), which is recognized by
a photoreactivating enzyme “photolyase”. The light energy (>380nm) is trapped by the antenna molecules of photolyase (such as MTHF/8-
HDF/FMN) and transfers them to catalytic cofactor FADH−which becomes excited and transfers energy to the pyrimidine dimer in the
form of e−, splitting the CPD into two monomeric unit, and then electron is transferred back to the flavin molecule.
absent or nonfunctional in placental mammals like human
[118, 132, 160]. However, Sutherland , Sutherland
and Bennett , and Harm  have demonstrated
photolyase activity in cells and tissues, including white blood
cells (WBCs) of several placental mammals, such as humans,
ox, cat, and mouse. A number of workers have identified
a human photolyase which shows homology with Cry gene
(plant blue-light receptor) and about 40% sequence identity
to the Drosophila 6-4 photolyase, but their exact roles in
repair process, whether it acts as a photolyase or as a
photoreceptors, are still under investigation .
DNA photolyases (45–66kDa) having 420–616 amino
acid residues  are monomeric flavin-dependent repair
enzymes, consisting of two known cofactors, a cat-
alytic cofactor and a light-harvesting cofactor. Till date,
5,10-methenyltetrahydrofolate (MTHF) , 8-hydroxy-5-
deaza-riboflavin (8-HDF) , and FMN  are known
as light-harvesting cofactors, which absorb light energy
efficiently and transfer them to FADH−. Deprotonated
reduced flavin adenine dinucleotide (FADH−) is found in
all known photolyases as a catalytic cofactor, which transfers
energy in the form of an electron to the CPD, splitting the
cyclobutane ring with the generation of two monomeric
bases [157, 167] (Figure 9).
In comparison to other eukaryotic systems, reports on
the repair of UV-induced DNA damage in plants are still
very limited. To avoid the deleterious effects of UVR, plants
have acquired two main protective strategies; shielding by
flavonoids and phenolic compounds [168, 169] and DNA
repair by photoreactivation. Photoreactivation mediated by
the enzyme photolyases is thought to be the major DNA
repair pathway in several higher plants such as rice, Ara-
bidopsis, wheat, and maize [170–172]. Studies on Arabidopsis
seedling, rice, and alfalfa indicate that photoreactivation
greatly enhances the rate of removal of dimers, although,
in the absence of photoreactivating (blue) light, dimers are
slowly eliminated from bulk DNA and 6-4PPs are generally
observed to be repaired more quickly than CPDs [173, 174].
Plants grown in the presence of photoreactivating radiation
can eliminate the majority of both 6-4 products and CPD
tion . The structural information about the interaction
between CPD lesions and photolyases became clear with the
help of X-ray crystallography  and nuclear magnetic
resonance (NMR) spectroscopy . However, how DNA
photolyases find lesions in the DNA molecule is still not clear
. It has been observed that about 240KJ/mol of energy
is captured upon absorption, out of which about 125KJ/mol
energy is consumed during the initial electron transfer from
the excited FADH to CPD lesions . The splitting of
CPD lesion proceeds rapidly within 0.6nanosecond [167,
178]. The back-transfer of electrons from the CPD lesion
to the FADH radical is efficiently avoided by the enzyme
before completion of cleavage of the cyclobutane ring .
With the help of ultrafast femtosecond laser spectroscopy,
enzyme is indeed left in the semiquinonid state after accom-
plishment of repair of the CPD lesion. However, Kavakli
and Sancar  have analyzed the role of intraprotein
electron transfer in photoreactivation by DNA photolyase
and found that photoreduction process is not a regular part
of the photolyase photocycle under physiological conditions,
because the enzyme may undergo at least 25 repair cycles
before loosing its activity. After completion of DNA repair,
a thymine pair is flipped back into the duplex DNA to form
a hydrogen bond with their complementary adenine base.
Fourier transform infrared spectroscopy (FTIR) has revealed
that the relaxation of DNA backbone proceeds very slowly
Journal of Nucleic Acids11
than the repair of CPD lesions . In the absence of
photoreactivating light, the enzyme binds to pyr <> pyr
and stimulates the removal of UV damage by stimulating
the NER system in vivo or in vitro and defense against DNA
damage even in the absence of light .
Unlike photoreactivation, excision repair is a multistep, dark
repair pathway, where an abnormal or damaged base is
removed by two major subpathways: (i) base excision repair
(BER) and (ii) nucleotide excision repair (NER).
10.1. Base Excision Repair (BER). BER is the predominant
DNA repair pathway against base lesions arising from
hydrolytic deamination, strong alkylating agents, ionizing
radiation (IR), or by different intracellular metabolites and,
indirectly, also by UV radiation via generation of ROS [182–
184] and proceeds through a series of repair complexes that
act at the site of DNA damage [185, 186]. The efficiency and
specificity of the repair pathway are determined by several
forms of DNA glycosylase which removes different types of
modified bases (Table 3) by cleaving the N-glycosidic bond
between the abnormal base and deoxyribose creating either
an abasic site or an SSB . Recently, Parsons et al. 
have discovered that the formation of DNA repair complexes
on damaged DNA stabilizes BER proteins. On the contrary,
by carboxyl terminus of Hsc70 interacting protein (CHIP)
and subsequently degraded by the proteasome.
The extent of BER conservation among E. coli and
mammals has led to progress in our understanding of
mammalian BER and here, a general overview of the
mammalian BER pathway will be discussed. As a result
of multiple interactions with a number of repair proteins
XRCC1 plays a crucial role in the coordination of BER
and SSB repair . The interaction between XRCC1
and polymerase β (Pol. β) and its functional aspects was
confirmed after UV-A-induced oxidative damage in living
mammalian cells . The AP-site is removed by the action
that breaks the DNA strand along 5?or 3?to the AP site,
respectively, and subsequently the gap is filled by a repair
DNA polymerase and the strand is joined by a DNA ligase
(Figure 10) [182, 191]. It has been reported that the repair
Pol. β itself has the capacity to excise the 5?deoxyribose
phosphate residues, that is, generated by the combined
actions of DNA glycosylase and ClassII AP endonuclease
. The major APE-1 that was discovered independently
as an abasic site-specific endonuclease homologous to the
E. coli Xth protein  incises duplex oligonucleotides
containing 5,6-dihydroxyuracil (DHU), 5-hydroxyuracil (5-
ohU), and alpha-anomeric 2?-deoxynucleosides (i.e., αdA
and αT) residues in human cells .
DNA having one nucleotide lesion is removed by
short-patch BER (SP-BER) whereas two/more nucleotide
lesion is repaired by long-patch BER (LP-BER) pathway
 (Figure 10). Recently, Almeida and Sobol  have
proposed a unified model of SP-BER and LP-BER. On the
basis of measuring the BER efficiency and presence of a
single modified base in a plasmid molecule transfected into
mammalian cells, Sattler et al.  made the first attempt
to verify the occurrence of LP-BER in vivo. It is assumed
that majority of repair takes place through SP-BER, initiated
either by monofunctional or by bifunctional glycosylase
involves the recruitment of poly (ADP-ribose) polymerase-1
(PARP-1) followed by scaffold protein XRCC1 and DNA pol.
β to replace the damaged nucleotide. DNA ligase III (Lig.
III) seals the nick and restores the intact DNA.
It has been observed that radiation- (X-rays, γ-rays)
induced breaks exist mainly as 5?p and 3?p at the margin of
the gap [197, 198] which is converted by the polynucleotide
for the DNA synthesis . Unlike SP-BER, LP-BER
involves proliferating cell nuclear antigen (PCNA) coupled
with DNA pol. −δ/ε or β which extends and fills the gap
by inserting 2–13 nucleotide . The replication factor C
(RF-C) is required to load PCNA onto the damaged DNA
. The flap endonuclease (Fen1) protein then displaces
the ensuing DNA flap leaving a nick which is ligated by DNA
ligase I (Lig. I) [200, 201].
In several plant species, some of the genes requisite
for dark repair have been identified [171, 172, 202–204].
The available evidence supports the additional existence of
enzyme-mediated excision-repair mechanisms in a variety of
systems including pollen, whole seedlings and plants, and
protoplasts derived from leaves and cultured cells [205, 206].
The formation of AP sites has been observed in seeds of
Zea mays during early germination. This phenomenon was
attributed to the action of DNA glycosylases on lesions accu-
mulated during seed storage , implying the presence of
BER in this species. Likewise, an enzyme activity attributed
to uracil-DNA glycosylase was found in cultured cells of
Daucus carota . Recently, it has been reported that the
mechanisms of BER and NER (but not photoreactivation) in
higher plants are active in proliferating cells .
10.2. Nucleotide Excision Repair (NER). NER is critically
important in the repair of UV-induced DNA lesions and is
one of the most versatile and flexible repair systems found in
most organisms but highly conserved in eukaryotes. It sorts
out a wide range of structurally unrelated DNA lesions, such
DNA-intrastrand crosslinks, and some forms of oxidative
damage, that cause helical distortion of the DNA double
helix as well as modification of the DNA chemistry and
the same NER proteins, the relative repair efficiency of both
of these lesions varies considerably in mammalian cells. It
has been established that in human and hamster cells, the
elimination of 6-4PP is at least fivefold faster than that of
Discovery of NER was first described in E. coli [212,
213] where about six proteins such as UvrA, B, and C
12Journal of Nucleic Acids
Table 3: DNA glycosylases and their probable substrate in bacteria, yeast, and human (modified from Sinha and H¨ ader ).
uracil from ss- and ds-DNA
U from U:G, ethenocytosine, hypoxanthine and
uracil from ss- and ds-DNA
uracil from ss-DNA, hydroxymethyluracil, formyluracil
3-methyladenine, 7-methylguanine, 2-methylcytosine,
(1) Uracil DNA glycosylase
(2) 3-methyl adenine DNA
S. cerevisiae MAG1
cis-syn-cyclobutane-type pyrimidine dimer
III/thymine glycol DNA
5-hydroxycytosine, thymine glycol, urea
oxidative DNA damage, thymine glycol and
formamido-pyrimidines, oxidized pyrimidines, 2
oxidative DNA damage, Thymine glycol and
formamido-pyrimidines residues, 5-hydroxycytosine,
oxidized pyrimidines, Me7-fapy-G
oxidized guanine lesions
Thymine, thymine glycol, urea, 5-hydroxycytosine,
dihydrothymine, and b-ureidoisobutyric acid
5-hydroxyuracil, 5-hydroxycytosine, 5,6-dihydrouracil,
thymine glycol, formamido-pyrimidines (FapyA/G)
5-hydroxyuracil and 5-hydroxycytosine
2,6-diamino-5-formamidopyrimidine 8-oxoG, 2
2-aminopurine/G and A/2-aminopurine, Adenine/C
Adenine from G:A, 8-oxoG:A, 2-hydroxyadenine
S. cerevisiae NTG1
(5) Endonuclease VIII
E. coli nei
E. coli fpg/mutM
(7) A-G-mismatch DNA
(8) G-T-mismatch DNA
Mig-MthThymine residues from T-G mismatches
Uracil from G:U
Thymine from T:G
Recognizes a G:T mispair in a CpG sequence
Journal of Nucleic Acids 13
Table 3: Continued.
(9) Formyluracil DNA
E. coli mug
Formyluracil mispaired with A & G
Formyluracil mispaired with G
Formyluracil mispaired with G
(10) Hydroxymethyl uracil
5-hydroxymethyluracil mispaired with G
ROS, alkylation, deamination,
IR (X-rays, γ-rays)
Modified base AP site SSB
DNA lig. III
DNA lig. I
Figure 10: Schematic overview of mammalian SP-BER (a), and LP-BER (b). SP-BER is initiated by the activity of glycosylase and APE1,
followed by scaffold protein XRCC1 and pol. β to remove the damaged nucleotide and DNA ligase III seals the nick. In case of LP-BER,
after DNA damage by ionizing radiation, PNK is recruited to convert the damaged ends to 3?OH and 5?P moieties. Here PARP1/2, followed
by XRCC1, is involved. PCNA and DNA pol. β and/or pol. −δ/ε extend and fill the gap by >2 nucleotides. Replication factor-C (RFC) is
required to load the PCNA on DNA. Ultimately the resulting 5?flap of DNA is removed by the flap endonuclease I (FEN1) and subsequently
the nick is sealed by DNA ligase I.
(known as ABC-complex, which shows excinuclease activ-
ity), UvrD (helicase II), DNA polymerase I (pol. I), and
DNA ligase are recruited to complete the repair [214, 215].
Eukaryotic NER is known to be similar to prokaryotes
regarding the biochemical strategy used but differs widely
in the nature and number of proteins used . The
eukaryotic NER pathway has extensively been studied at
the molecular level in yeast and human cells. A schematic
representation of the NER pathway in human is illustrated
in Figure 11.
14Journal of Nucleic Acids
RNA pol. II
Ligase III / XRCC1
RNA pol. II
Strand unwinding and
processing of damaged
Figure 11: Molecular mechanisms of global genome nucleotide excision repair (GG-NER) and transcriptional coupled nucleotide excision
repair (TC-NER) in mammals. For details see the text.
NER can be subdivided into differentially regulated
subpathways such as global genome NER (GG-NER) and
transcription-coupled NER (TC-NER): repair of lesions over
the entire genome, referred to as global genome repair
(GGR), and repair of transcription-blocking lesions present
in transcribed DNA strands, referred to as transcription
coupled repair (TCR). Both repair systems removed a wide
range of UV-induced DNA lesions in a sequential way that
includes damage recognition, opening of DNA double helix
at damage site, and dual incisions on both sides of the lesion
followed by resynthesis and ligation [210, 216] (Figure 11).
In human XP-C cells, where the removal of 6-4PP takes place
through the TCR pathway, the repair seems to be threefold
slower as compared to normal cells. This indicates that the
GGR is the most preferred and efficient pathway for 6-4PP
gradually, whereas TCR, which is firmly linked to RNA
polymerase II (RNA pol II) transcription, is highly specific
and efficient. NER defects are associated with a surprisingly
wide clinical heterogeneity.
It is assumed that TC-NER proceeds when the tran-
scription machinery RNA pol II encounters a lesion. To
progress the transcription-coupled repair (TCR), the stalled
polymerase must be displaced, which is brought about by
the recruitment of two proteins CSA and CSB. The CSA
protein (44kDa) which belongs to “WD repeat” family
of proteins exhibits structural and regulatory roles and
CSB proteins (168kDa) which belong to SWI/SNF family
of proteins exhibit DNA-stimulated ATPase activity [217–
219]. As stated earlier, elongation of active RNA pol II
is prerequisite for efficient TCR; the CSA and CSB gene
products are required for efficient repair only during the
elongation stages of RNA pol II transcription. It has been
suggested that the RNA pol II backs up some nucleotides
upon encountering the lesion to facilitate the accessibility
of the repair machinery to the lesion site [220, 221]. It
is expected that the CSB protein ubiquitinates the stalled
elongating RNA pol II complex at the lesion and enhances
the assembly of repair factors . However, the fate and
the role of ubiquitylated RNA pol II have yet to be clarified
. Recently, Fousteri et al.  has revealed that CSB is
a prerequisite factor in vivo to assemble NER proteins while
it is not essential to recruit TFIIH or NER complex in vitro.
In living human cells, Proietti-De-Santis et al.  have
shown that CSB is required during the first phases of RNA
(i.e., used for 6-4PP detection), elongation of RNA pol II is
greatly impaired, affecting the efficiency of TCR. Hence, at
higher UV radiation the GGR overrules the TCR pathway
. The probable relationship between TCR and blockage
of RNA transcription subsequent to UV-irradiation may
Journal of Nucleic Acids15
Figure 12: Different pathway for recognition of DNA lesions such
as CPD and 6-4PP. In case of CPD photoproduct (cause little
distortion), XPC complex binds to the lesion after recruitment of
UV-DDB whereas 6-4PP that distorts the DNA helix to a great
extent can be recognized either by interacting with prebound UV-
DDB or directly by XPC complex.
factor at both levels, allowing either the recruitment of
the transcription machinery at the initiation sites or the
remodeling of the stalled RNA polymerase allowing the NER
factors to access the lesion .
In GG-NER pathway, lesions produced in transcription-
ally silent areas of the genome are recognized by hHR23B-
XPC protein complex in an energy-independent manner.
The rate of GGR strongly depends on the type of lesion. For
instance, 6-4PPs are removed much faster from the genome
than CPDs, possibly because of disparity in affinity of the
damage sensor hHR23B-XPC. XPC is the sole XP factor
not essential for TCR and is restricted to GGR . It
is supposed that XPC binds preferentially to the stretch of
ssDNA that occurs in the nondamaged strand, opposite to
a lesion . However, association of UV-damaged DNA-
binding protein (UV-DDB) with a cullin-based ubiquitin
ligase has revealed novel mechanistic and regulatory aspects
of mammalian GG- NER. It was reported that XPC and
UV-DDB materialize to assist for the efficient recognition
of UV-induced photolesions and that both factors are
ubiquitylated [250, 253]. Lesions that cause little distortion
can be recognized by the DDB complex which is also part
of an E3 ubiquitin (Ub) ligase that poly-ubiquitinates XPC
and XPE . A mechanistic pathway for recruitment of
XPC complex to the major UV-induced photolesions (i.e.,
CPDs and 6-4PPs) has recently been elucidated [216, 253].
It was shown that DDB complex is recruited first to the
lesion (CPD) before the XPC complex, on little distorted
DNA helix; however, in case of large distortion of the DNA
helix caused by 6-4PPs, direct recognition by XPC is also
possible for this lesion (Figure 12) [216, 253]. However, the
method by which XPC locates a lesion in the vast excess
of undamaged DNA in the enormous mammalian genome
is not clear  and it needs more investigation. On
the basis of DNase I footprinting, Sugasawa et al. 
showed that hHR23B-XPC attaches directly to DNA damage
and alters the DNA conformation around the lesion. The
XPC protein (125kDa) is complexed with hHR23B protein
(58kDa). These two proteins are human homologs of the
yeast (S. cerevisiae) NER factor Rad4 and Rad23, respectively
(Table 4). In mammalian cells, the quantity of hHR23B is
higher than the XPC  and in vitro activation of the
hHR23A can substitute for hHR23B in complex formation
and stimulation of XPC repair activity . Both hHR23A
and -B harbor a ubiquitin-like moiety at their amino
a similar high affinity for both UV-induced single-stranded
DNA (ssDNA) and double-stranded DNA (dsDNA) [230,
259], preferentially binds to DNA with various lesions 
and even to small bubble structures with or without a lesion
. hHR23B-XPC is absolutely required for dual incision
as well as for open complex formation during GG-NER [243,
261]. Overall, it has been distinguished that RNA pol II with
the TCR while hHR23B-XPC complex is the first factor
in NER that initiates GGR by sensing and binding lesions,
locally distorting the DNA double helix and recruiting the
other factors of the system .
After initial steps of damage recognition, the subsequent
unwinding of DNA double helix at the site of lesion takes
place by the components of multi-subunit transcription
factor-IIH (TFIIH). TFIIH is a ten-subunit protein complex
(Table 4) composed of a core complex (XPB, XPD, p62,
p44, p34, p52, p8) and of a cdk activating kinase (CAK)
subunit (Mat1, Cdk7, CyclinH) . TFIIH is usually
involved in initiation of RNA Pol II transcription, but upon
DNA damage can be employed in cell cycle regulation and
NER (both in global genome and TC-NER) [228, 235].
Two subunits of TFIIH such as XPB (3?to 5?helicase)
and XPD (5?to 3?helicase) are responsible for opening of
DNA double helix around the lesion in an energy (ATP)
dependent manner. It has been found that the XPD helicase
activity is dispensable for in vitro transcription  but
seems to play an additional architectural role within the
[228, 236]. After opening of DNA double helix by TFIIH,
three proteins such as RPA, XPA, and XPG are recruited.
The exact order of assembly of these proteins is not clear.
Both XPA and RPA can recruit with the DNA lesions in
absence of XPG, and similarly XPG can also join the damage
sites in the absence of XPA [238, 239]. Moreover, XPA and
heterotrimeric replication protein A (RPA; RPA70, 32 and
14) are recruited to confirm the presence of DNA damage
and form a more stable preincision complex . RPA
was found to be required both for the dual incision and
for the repair synthesis steps of NER . It was assumed
that RPA binds the nondamaged strand of the opened DNA
bubble, thus allowing exact positioning and stimulation of
the endonuclease activities of XPG and ERCC1-XPF [246,
247]. XPG, which belongs to flap endonuclease-1 (FEN-
1) family of structure-specific endonucleases , is not
only involved in performing the 3?incision in NER but also
required for stabilizing the fully open DNA bubble structure
16Journal of Nucleic Acids
Table 4: NER proteins and their probable role in human and S. cerevisiae.
HumanYeast S. cerevisiaeSize (a.a)
Binds damaged DNA; recruits other NER
proteins; works with hHR23B. involved
only in GGR
Stimulates XPC activity in vitro; contains
[22, 226, 227]
Can substitute for hHR23B in vitro
Stabilizes the XPC-hHR23B complex
[227, 232, 233]
[227, 233, 234]
p34TFB4 303[227, 228, 235]
[227, 228, 233]
Core TFIIH subunit
[227, 228, 236]
Core TFIIH subunit
[227, 228, 233, 236]
CDK assembly factor; CAK subcomplex
CDK, C-terminal domain kinase; (CAK)
subcomplex; phosphorylates RNA pol. II
and other substrates
Cyclin; CAK subcomplex
TFB5/TTDA (p8)Tfb5 71
Binds damaged DNA and facilitates
repair complex assembly; affinity for
[183, 238, 239]
Stabilizes opened DNA complex;
positions nucleases; ssDNA binding
Stabilizes opened DNA complex;
positions nucleases; ssDNA binding
Stabilizes open complex (with
Endonuclease (catalyzes 3?incision);
stabilizes full open complex
RPARPA32 Rfa2 270[227, 240–242]
RPA14 Rfa3 121[22, 240, 241]
Part of structure-specific endonuclease;
catalyzes 5?incision; interstrand
Part of endonuclease (5?-incision);
recombination via single-strand
[227, 246, 249]
[228, 250, 251]
and to permit the 5?incision by ERCC1- XPF . Subse-
quently, the injured part of the DNA is removed by cleaving
the damaged strand towards 3?and 5?of the lesion by
endonuclease XPG and XPF/ERCC1 complex, respectively,
generating a 24–32 base oligonucleotide fragment . It
has been found that E2F1 plays a direct, non-transcriptional
role in DNA repair involving increased recruitment of NER
factors to sites of UV-induced DNA damage . Finally
the gap is filled by DNA polymerase δ or ε (along with
some accessory proteins, like PCNA and RFC) and sealed
by DNA ligase. It is assumed that ligase-I is responsible for
ligation of remaining nick , but very recently it has
been reported that mostly ligase III, in cooperation with its
partner XRCC1 seals the DNA nicks and ligase I plays a
minor role in actively replicating cells, but not in quiescent
cells . Recently, several workers have tried to dissect
the molecular mechanisms of TC-NER [216, 223, 244, 269].
In spite of the above facts, more investigations are still
required to improve our understanding of the GGR and TCR
Journal of Nucleic Acids 17
Several observations provide evidence that “dark” repair
of UV-induced NER is a significant DNA repair mechanisms
in plants that is capable of excising dimers, particularly 6-
4PPs [30, 270]. Genetic and genomic analysis indicates that
plant NER pathway is homologous to that of mammals
and fungi and unrelated to the bacterial system [204, 271–
273]. Based on the reduction of nuclear CPD frequency, the
presence of NER has been reported to occur in several plants
such as Glycine max and cultivars of Oryza sativa [274, 275].
Furthermore, CPDs were found to be excised from the
nuclear DNA of Daucus carota and Wolffia microscopia at
animal cells [205, 275]. A UV-specific endonuclease resem-
bling UvrABC nuclease in activity was partiallycharacterized
from spinach . Classical genetic analysis has resulted in
the identification of at least four complementation groups
required for this repair in Arabidopsis (UVR1, UVR5, UVR7
await further genetic and phenotypic characterization .
Moreover, a plant homologue of human NER gene of
the endonuclease, ERCC1, has been cloned from Lilium
longiflorum which showed a similar role in DNA repair in
It is one of the widespread mechanisms which efficiently
repair double-strand breaks (DSBs) and single-strand gaps
in damaged DNA by a series of complex biochemical
reactions, as a result of ionizing radiation, UVR, ROS,
and chemotherapeutic genotoxic chemicals . The lethal
effects of double strand breaks (DSBs) can be conquered
by the existence of two independent pathway, such as
homologous recombination (HR) and non-homologous end
joining (NHEJ). Multiple proteins are required for DSB
repair by recombination, which are conserved among all
eukaryotes and deficiencies in this repair mechanism can
cause hereditary diseases. For instance, mutation of at least
one of these repair proteins, called BRCA1 may lead to
could be one of the key players in DNA damage response
. DSB repair through HR process is an error free
pathway, since, it requires an extensive region of sequence
homology between the damaged and template strands,
whereas NHEJ is an error prone, alternate pathway for the
repair of DSBs, essentially joins broken chromosomal ends
independent of sequence homology.
12.1. Homologous Recombination. Repair of DSBs by HR
requires the genes of “RAD52 epistasis group” such as
RAD50, RAD51, RAD52, RAD54, RAD55, RAD57, RAD59,
MRE11 and XRS2, which were first defined in yeast Sac-
charomyces cerevisiae mutants. Homologues of most of the
genes are highly conserved among all eukaryotes including
human [282, 283] highlighting these genes for cell survival.
Among all, E. coli recA gene and its eukaryotic homologs
RAD51s are the best recombination genes . The recA
gene encodes a DNA-dependent ATPase that binds to
ssDNA and promotes strand invasion and exchange between
homologous DNA molecules . Among eukaryotes,
the yeast S. cerevisiae and Schizosaccharomyces pombe have
four RAD51-like genes (RAD51, DMC1, RAD55/rhp55, and
RAD57/rhp57) [286, 287] whereas vertebrate animals and
plants have seven types of RAD51-like genes (RAD51,
-51B, -51C, -51D, DMC1, XRCC2, and XRCC3) . The
genome integrity in both mitotic as well as meiotic cell cycle
[288, 289]. There are 59% identity between S. cerevisiae,
human and mouse in the case of Rad51 protein (Rad51p)
and 30% identity to RecA protein of bacteria , whereas
yeast and human proteins are 60% identical in case of
Rad52 proteins (Rad52p) . Yeast cell can exhibit both
“allelic” [292, 293] as well as “ecotopic recombination”
[294, 295] to repair a broken chromosome. Recombinational
repair is a significant UV-tolerance mechanism in plants
where UV-induced chromosomal rearrangements including
homologous intrachromosomal recombination events have
been found . In mammalian cells the recombinational
pathway of DSBs, seems to be operated in late S- and G2-
phase, when DNA molecules are replicated and spatially
The first step of DSB repair via HR is the resection
of 5?ends to produce a 3?ssDNA overhang by means of
an exonuclease (such as RecBCD in E. coli, MRX-complex
in S. cerevisiae and MRN-complex in vertebrates). Rad51
(a functional homolog of the E. coli RecA)  is the
central protein in HR, binds the exposed single-stranded
tails forming a nucleoprotein filament and this early step
is promoted by a Rad55/Rad57 protein heterodimer 
by overcoming the inhibitory effects of the heterotrimeric
single-stranded DNA binding protein RPA . Recently,
it has been reported that a member of the histone H2A
family, γ-H2AX protein plays an important role in the
recruitment of Rad51 protein in HR in eukaryotes .
The Rad51 nucleoprotein filament in association with other
repair protein searches the genome for an intact copy
of the broken DNA on the sister chromatid to form a
heteroduplex joint molecules or D-loop that is matured
in to a Holliday junctions (HJs). HJ is then resolved to
give crossover products (Figure 13). In E. coli, this HJ is
in eukaryotic cell, how this HJ is resolved to give crossover
products is not known. In S. cerevisiae, DNA DSB repair by
the joint molecule formation is followed by extension of
the incoming strand by DNA polymerases and branch
migration, leading to restoration of the genetic information
12.2. Non-Homologous End Joining. When HR is inactivated,
an alternate pathway, that is, NHEJ becomes operative
for the repair of DSBs , that also involves a multi-
protein complex and has been found in organisms ranging
from a few prokaryotes to mammals. This suggests that
this mechanism has been conserved during the course of
18Journal of Nucleic Acids
IR, UVR, ROS
Homology search and formation
of Joint molecules with
DNA ligation and resolution
of holliday junction
End processing by 5?
to 3?ssDNA resection
(a) NHEJ(b) HR
Figure 13: Schematic representation of recombinational repair by (a) non-homologous end joining (NHEJ), and (b) homologous
evolution, although, most of the protein factors, involved in
NHEJ were initialy identified in the mammalian cells .
have ligatable termini, hence requires the action of nucleases
and DNA polymerases to generate them. The participation
of DNA polymerase in the NHEJ pathways is still a matter of
debate, however in vitro biochemical analysis in mammals,
suggest that DNA polymerase λ (Pol. λ) and/or polymerase
μ (Pol. μ) participates in NHEJ process at incompatible
DNA ends [80, 305, 306]. The NHEJ process is initiated by
the binding of specific protein to the broken ends, which
may acts as end bridging factor . It has been shown
that Ku complex (a heterodimer of Ku70/Ku80 [≈86]) is
a major end binding factor in mammalian cells, possess
end bridging activity [308, 309]. The catalytic subunit of
DNA protein kinase (DNA-PKcs) is required in mammalian
NHEJ to bridge the DNA ends through their protein-protein
interactions [310, 311]. Cells lacking functional DNA-PK
components are known to have elevated sensitivity toward
UV irradiation .
Association of DNA-PKcs is followed by the recruitment
of other repair proteins (such as ligaseIV/Xrcc4, Artemis,
PNK and Polymerase X) to proceed the NHEJ repair 
(Figure 13). Recently, a third protein, designated as XLF
or Cernunnos  that has homology to Xrcc4, has
been identified and shown to co-associate with the DNA
ligaseIV/Xrcc4 complex [314, 315]. Artemis, a member of
β-lactamase superfamily, has 5?→ 3?exonuclease activity.
In the presence of DNA-PKcs, Artemis can also function as
→ 3?endonuclease. It has been found that Artemis
dependant DSB rejoining also requires ATM, Mre11-Rad50-
Nbs1 (MRN) complex, 53BP1 and H2AX [316–318]. The
yeast Hdf1/2 and Dnl4/Lif1 are the functional homology
of mammalian Ku and DNA ligaseIV/Xrcc4, respectively.
DNA ligase IV is absent in bacteria, however, in Bacillus
subtilis, the gene ykou/v has been found that encodes a
Journal of Nucleic Acids19
SOS gene promoter
all SOS responding gene
Failure of repair
Expression of RecA protein
all SOS responding gene
DNA Pol. V/IV
activate the auto breakdown of LexA proteins, allowing the induction of all SOS responding genes. The pathway of SOS response is reversed
when damages are repaired through the damage specific mechanisms. Here the inactivation of RecA protein allows the accumulation of
LexA, which bind to SOS promoters and repress all SOS responding genes. SOS response is highly mutagenic due to involvement of DNA
polypeptide with ligase, primase and nuclease domains.
Genetic and biochemical evidence suggest that Mre11-
Rad50-Xrs2 (MRX) act as end bridging factor in yeast NHEJ,
since DNA-PKcs is absent in them [319, 320]. In case of
bacteria, the Ku proteins occur in homodimeric forms and
. Recombinational repair is a significant UV toler-
ance mechanism in plants where UV-induced chromosomal
rearrangements including homologous intrachromosomal
recombination events have been found . Very few of the
plant genes involved in DSB repair have been identified. The
sequence of an Arabidopsis Rad51 homologue has been made
available . It has been suggested that as in mammals,
breaks are repaired by nonhomologous recombination far
more frequently than via HR [202, 323].
The accumulation of massive amount of DNA lesions within
the cells under different specific physiological responses
 may lead to the occurrence of SOS repair system which
was well described in E. coli, where the involvement of more
than 40 genes have been found . It has been found that
the bacterial NER is linked with all DNA damage response
through a network of reactions, known as SOS response
The accumulation of DNA lesions may interfere with
replication process, prompting cells to stop division, there-
fore giving time to the cell to repair damaged DNA and
proceeds DNA replication process . SOS repair system
is initiated by interaction of two crucial proteins the RecA
and the LexA repressor which curbs the expression of SOS
genes by binding to their promoters  (Figure 14).
The proteolytic activity of RecA protein inactivates the
LexA repressor and induces all the genes to which LexA
is associated. A number of genes (or operon) collectively
known as din (damage inducible) gene such as uvrA, uvrB,
cho (uvrC homolog) and uvrD of E. coli NER take part in
SOS response [325, 328]. The SOS response is induced with
damage signal but it is highly mutagenic due to engagement
 and DNA polymerase IV  in E. coli. Interestingly,
it has been found that DNA polymerase IV (dinB) is also
involved in translesion synthesis in E. coli . Majchrzak
et al.  examined the effects of SOS response on genome
observed that SOS response genes destabilized the TRS tracts
and also altered the superhelical density of the plasmids.
Recently, the genes imuA and imuB have been described that
SOS repair system has still to be investigated.
In response to diverse genotoxic stresses such as UV radi-
ation, IR, chemicals used in medical therapy, by-products
of intra-cellular metabolism, several protective mechanisms
20Journal of Nucleic Acids
damaged DNA By
Figure 15: Schematic illustration of DNA damage-induced cell-cycle checkpoint activation (for details, see text).
including processes of DNA repair, Cell-cycle checkpoint
the organisms to secure the genomic integrity. DNA damage
4PPs), strand breaks (DSBs/SSBs) may stop the progression
of cell-cycle temporarily to give opportunities to the cell for
DNA repair before replication or segregation of the affected
chromosome , or may induce an apoptotic program
to eliminate the damaged cells to avoid their carcinogenic
potential . ROS may induce several types of DNA
lesions such as DSBs and SSBs, DNA-DNA and DNA-
protein cross links and base modifications . It has been
via aberrant processing of a DNA DSBs. Hence forth, we
discuss the DSBs/SSBs-induced cell-cycle checkpoint arrest
in eukaryotes mainly in mammals that play a critical role in
preventing chromosomal instability. Regulation of cell-cycle
checkpoint proceeds through a network of damage sensors,
signal transducers, mediators, and various effector proteins
. Phosphatidylinositol-3 (PI3)-kinase related kinases
(PIKKs) ATM (ataxia telangiectasia mutated) protein, ATR
(ATM and Rad3 related) protein, and DNA-PK, with effector
proteins mediated cell-cycle checkpoint arrest (at G1/S,
G2/M, and intra S-phase), DNA repair and cell death have
been observed in mammalian cells . It has been shown
that ATM and DNA-PK are activated by the presence of
DSBs where as activation of ATR takes place by single
strand regions of DNA [337, 338]. Activation of both ATM
and ATR results in phosphorylation of Chk2 and Chk1
respectively which transfer the DNA damage signal to the
cell-division cycle proteins Cdc25(A-C). Phosphorylation
of Cdc25 by Chk1/Chk2 leads to its ubiquitin mediated
The prevailing evidence suggests that damage response
mediated activation of ATM/ATR either directly or via Chk2
phosphorylates p53, which transcriptionally activates the
Cdk inhibitor, p21, which arrest G1/S cell-cycle checkpoint
. Recently, it has been reported that DNA damage
caused by UV radiation or ROS such as hydroxyl (OH) free-
radical results in ATM mediated phosphorylation of BID
protein that induce cell-cycle arrest in S-phase [339, 340].
The occurrence of DNA damage response in G2-phase,
leads to checkpoint mediator (claspin) dependent activation
of Chk1/2, followed by SCFβTrcPmediated degradation of
CDK-activating phosphatase Cdc25A [341, 342], that results
in arrest of multiple cell-cycle transition including the G2
checkpoint [343, 344]. The ubiquitin mediated destruction
of claspin and WEE1 (both proteins have conserved β-
TrcP phosphodegrons) eliminates the essential coactivator
of Chk1 and CDK inhibitor respectively allowing reaccu-
mulation of Cdc25A followed by Cdc25B and C, which
results in activation of cyclin-Cdk (cyclinB-Cdk1) complex
. Under normal conditions, this latter complex being
active promotes G2/M transition and upon inactivation due
to DNA damage, blocks the G2 cell-cycle and unlike the
G1/S checkpoint this arrest seems to be partly p53/p21
Journal of Nucleic Acids21
independent . The intermediate component of this
 and claspin [347–349] with the SCF ubiquitin ligase
complex and this SCFβTrcPacts as trigger of checkpoint initi-
after Chk1 mediated Phosphorylation of Cdc25A ,
as well as checkpoint recovery which is linked with Plk1
mediated phosphorylation of claspin and WEE1 [347, 348].
Although, the exact mechanism(s) regarding the reactivation
of Plk1 during checkpoint recovery is still in dispute. The
malfunctioning of cell-cycle checkpoint as a result of chronic
damage and/or defects in DNA damage response (DDR)
components such as p53, p21, ATM, Chk2, BRCA1/2 tumor
suppressors, may induce several types of human disorder at
the expence of enhanced genomic instability .
In addition to the above mentioned repair mechanisms
several other repair machineries such as mutagenic repair
(or lesion bypass) and programmed cell death (PCD)
or apoptosis may become effective for the recovery of
genome against constant attack of numerous genotoxins.
UV-radiation, ionizing radiation and various chemicals are
responsible for most of the mutagenesis due to a process of
translesion synthesis in which a polymerase or replicative
assembly encounters a noncoding or miscoding lesion,
inserts an incorrect nucleotide opposite the lesion and
then continues elongation . It has been reported that
translesion synthesis past a CPD, facilitated by pol. η, with
the insertion of adenines opposite both bases of a T∧T
CPD , where as 6-4TT may lead to a G insertion. In
Saccharomycescerevisiae,pol.η andpol.ζ (consistingofRev3
and Rev7 proteins) has been reported to replicate across a
T∧T CPD . Polymerase η (pol. η) can also replicate
across a basic sites, AAF (acetylaminofluorene), guanine
adducts and cis-platinated guanines .
When the repair mechanisms are unsuccessful, it may
cause cellular senescence (permanent cell cycle arrest), onco-
genesis or apoptosis . Apoptosis plays an essential role
in survival of the organisms by preventing the multiplication
of mutated chromosomes, normal embryonic development,
elimination of indisposed cells and maintenance of cell
R. P. Rastogi acknowledges University Grants Commission,
New Delhi, India, for financial support in the form of a
fellowship. Works related to UV-B radiation effects are partly
supported by the project grant sanctioned by Department
of Science and Technology, Govt. of India, New Delhi
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