DNA Repair 2 (2003) 947–954
p53 and regulation of DNA damage recognition during
nucleotide excision repair
Shanthi Adimoolam, James M. Ford∗
Departments of Medicine (Oncology) and Genetics, Stanford University School of Medicine,
1115 CCSR Building, 269 Campus Drive, Stanford, CA 94305, USA
Received 17 April 2003; accepted 23 April 2003
In response to a variety of types of DNA damage, the p53 tumor suppressor gene product is activated and regulates a
number of downstream cellular processes such as cell cycle arrest, apoptosis and DNA repair. Recent discoveries concerning
the regulation of DNA repair processes by p53, such as nucleotide excision repair (NER) and base excision repair (BER) have
paved the way for studies to understand the mechanisms governing p53-dependent DNA repair. Although several theories
have been proposed, accumulating evidence points to a transcriptional regulatory role for p53 in NER, mediating expression
of the global genomic repair (GGR)-specific damage recognition genes, DDB2 and XPC. In BER, a more direct role for p53
has been proposed, potentially acting through protein–protein interactions with BER specific factors. These advances have
greatly enhanced our understanding of the role of p53 in DNA repair and this review comprehensively summarizes current
opinions on the mechanisms of p53-dependent DNA repair.
© 2003 Elsevier B.V. All rights reserved.
Keywords: p53; Nucleotide excision repair; Global genomic repair; XPC; DDB2; DNA damage
The discovery of the p53 tumor suppressor gene
over 20 years ago has led to a plethora of inves-
tigation to understand the basic biology behind its
role in maintaining genomic stability and the cellular
response to DNA damage. p53 is one of the most
commonly mutated genes in human cancers  and
its product is a multifunctional protein that regulates
several physiological processes including cell cy-
cle checkpoints, apoptosis and DNA repair . The
structure-to-function relationships in p53 have been
very well characterized and the primary sequence
∗Corresponding author. Fax: +1-650-725-1420.
E-mail address: firstname.lastname@example.org (J.M. Ford).
can be subdivided into several functional domains:
transcriptional activation, sequence-specific DNA
binding, DNA damage recognition, protein–protein
interactions and the C-terminal regulatory domain
. A variety of tumor-derived mutations have been
identified in several of these domains and have been
instrumental in elucidating their associated functions
. The primary role of p53 in tumor suppression
has been attributed to its function as a transcription
factor, regulating expression of over one hundred
different cellular genes , although protein–protein
interactions may also play a role. In response to a
variety of genotoxic stimuli, p53 protein is stabilized
through a series of posttranslational modifications ,
is activated for sequence-specific DNA binding and
transcriptionally regulates downstream target genes
1568-7864/$ – see front matter © 2003 Elsevier B.V. All rights reserved.
S. Adimoolam, J.M. Ford/DNA Repair 2 (2003) 947–954
that contain a consensus p53 response element in their
promoter or intronic segments. The p53-regulated
cyclin-dependent kinase inhibitor p21 is a primary
mediator of the p53-dependent G1 cell cycle arrest
following DNA damage , although this response is
likely also governed by other p53 target genes. Con-
versely, p53 can induce expression of a wide array
of genes involved in the apoptotic pathway, signify-
ing that the apoptotic response is mediated through
the synergistic action of numerous p53-induced sig-
nals , and is also potentially complemented by
additional p53 transcription-independent effects on
2. p53 is critical for nucleotide excision
Due to an improved understanding of the roles of
p53 in cell cycle progression and apoptosis, it became
apparent that cells with defective p53 function may
fail to arrest in G1 or lack the ability to eliminate cells
through apoptosis following DNA damage . This
could in turn lead to an accumulation of mutations
in DNA and contribute to overall genomic instability
and cancer susceptibility. To further explore the role
for p53 in protecting the cellular genome, we eval-
uated a possible direct effect of p53 on the removal
of potentially mutagenic lesions upon DNA damage
by the human nucleotide excision repair (NER) path-
way. NER is an evolutionarily conserved DNA repair
pathway with the ability to remove a wide range of
DNA adducts induced by environmental as well as
endogenous sources , the most relevant being the
UV-induced cyclobutane pyrimidine dimers (CPDs)
and the (6-4) pyrimidine–pyrimidone photoproducts
(6-4PPs). The process of NER is subdivided into two
genetically distinct pathways: repair of lesions over
the bulk genome, referred to as global genomic repair
lesions present in transcribed DNA strands, known as
transcription-coupled repair (TCR) . We therefore
examined NER activity in Li-Fraumeni syndrome
(LFS) fibroblasts heterozygous for mutations in p53,
as well as in derived sublines expressing only mutant
p53 . The homozygous p53 mutant cells were in
fact deficient in GGR following UV-C irradiation, but
proficient for TCR. The requirement for p53 in NER
was also observed by Smith et al. , using host cell
reactivation experiments with reporter plasmids and
in vitro DNA repair assays. At the same time, Wang
et al.  reported the direct binding of p53 to the
NER factors XPB and XPD and inhibition of their
helicase activity, and noted reduced repair of CPDs in
LFS heterozygous p53 mutant cells. Since these ini-
tial reports, we and numerous other investigators have
confirmed the role for p53 in GGR in a variety of
human and mouse cell types [16–23]. In addition, p53
has been found to be important for NER of other DNA
adducts, including the tobacco carcinogens BPDE and
BCDE [24–26]. From these various observations, we
initially speculated that one potential mechanism for
p53-dependent NER is through transcriptional regula-
tion of NER genes . However, the observations by
Wang et al. suggested that p53 might also modulate
NER through protein–protein interactions, by direct
binding to the TFIIH helicases XPB and XPD .
Jayaraman and Prives  proposed an alternate
mechanism involving direct binding of the C-terminus
of p53 to altered DNA structures, which in turn could
activate p53 for sequence-specific DNA binding and
gene transcription. In this review, we will summarize
accumulating evidence that indicates that p53 may
function as a transcription factor to regulate NER
genes participating in GGR [28–30].
3. p53 acts as a transcription factor in NER
Due to the differential modes of damage recogni-
tion in GGR versus TCR , and the selective ef-
fect of p53 on GGR, we initially speculated that p53
may be involved in regulation of GGR-specific DNA
damage recognition factors . In fact, strong evi-
dence now points to a transcriptional regulatory role
for p53 in NER, similar to that observed in other
p53-regulated biological pathways. For example, we
demonstrated that p53 transcriptionally regulates ex-
pression of the DDB2 gene mutated in XPE , and
along with others, showed that overexpression of the
DDB2 gene product, p48, enhances GGR in the con-
text of p53 deficiency [31–33]. The identification of
a region in the human DDB2 gene that binds and re-
sponds transcriptionally to p53 further confirmed the
direct activation of the DDB2 gene by p53 . XPC
is another GGR-specific gene whose protein product
S. Adimoolam, J.M. Ford/DNA Repair 2 (2003) 947–954
is involved primarily in 6-4PP recognition , but is
nevertheless required for CPD removal [36–38]. We
recently reported the regulation of XPC by p53 in re-
sponse to DNA damage, and showed that the mRNA
and protein products of XPC increased in a p53 and
firmed by gel shift assays  and promoter–reporter
assays (unpublished data) that p53 regulation of XPC
occurred primarily through a p53 response element lo-
cated in the promoter of the XPC gene. These results
along with the observations with DDB2 overexpres-
sion in a p53 deficient or non-functional background
[32,33], signifies that p53-regulated NER genes can
rectify the GGR deficiency associated with lack of
functional p53. Similarly, the p53-regulated gadd45
gene contributes to GGR activity but is not required
for TCR , although its mechanistic role in GGR
remains unclear. Therefore, p53 appears to control the
damage recognition step in GGR through the coordi-
nate regulation of genes involved in lesion binding.
4. The p53-regulated DDB2 and XPC gene
Thus far, the regulation of GGR by p53 appears to
be confined to the lesion recognition step in GGR, pri-
marily through transcriptional control of DDB2 and
XPC gene expression. XPC is found in vivo in tight
association with its coactivator protein, hHR23B, and
this complex is dispensable for TCR but required for
efficient GGR [36,37]. XPC–hHR23B has a strong
binding affinity for certain lesions including 6-4PPs
[39,40], but recognizes CPDs to a significantly lesser
extent in vitro. However, XPC is absolutely required
for CPD (and 6-4PP) removal in vivo , indicat-
ing that additional factors maybe required for CPD,
but not 6-4PP recognition [35,40]. The XPC binding
partner hHR23B appears to be involved in mod-
ulating both the stability of XPC [41,42], as well
as in regulating the binding of XPC to damaged
DNA . Similarily, in vitro gel shift analyses have
demonstrated a strong binding affinity for 6-4PP by
the UV–DDB complex comprising the two subunits
p48/p127 encoded by the DDB2 and DDB1 genes
respectively, but a significantly weaker binding to the
CPDs . However, the repair phenotype of XPE
cells is similar to p53-deficient cells, with a selective
reduction in repair of CPDs but not 6-4PPs . Both
XPC and p48 basal and inducible levels are regulated
at the level of transcription by p53 [28,29]. In addi-
tion, p48 is degraded by the proteasome as an early
event after UV-irradiation [33,45], indicating an ad-
ditional posttranscriptional mechanism of regulation.
Correspondingly, the stability and activity of the XPC
gene product appears to be dependent on the presence
of its binding cofactor hHR23B [41–43]. Lommel and
coworkers  have shown that the yeast homolog of
XPC, Rad4 is ubiquitinated in vivo and that Rad23
contributes to its stability by acting as an inhibitor
of multi-ubiquitin chain assembly. Thus, it is appar-
ent that the damage recognition process in GGR is
regulated at multiple levels, through transcriptional
control by p53, and at the posttranslational level by
Several recent studies have investigated the time-
line of events occurring during lesion binding and
repair in the GGR pathway. We and others [32,46,47]
have shown that p48 and XPC proteins localize to
sites of UV-induced lesions within minutes follow-
ing UV-irradiation, and that the binding of XPC is
accelerated when p48 is present. Following this obser-
vation, we have also now demonstrated (Fitch et al.,
unpublished results) in NER-deficient XPA cells sta-
bly expressing heterologous photoproduct-specific
photolyases that p48 binds in vivo to both CPDs and
6-4PPs with comparable efficiency, whereas XPC is
unable to bind to CPDs unless p48 is present. As men-
tioned, basal levels of both p48 and XPC are higher
in cells with wildtype p53, suggesting that basal lev-
els of these factors are important for determining the
initial rate of GGR, predominantly for the rapid re-
moval of 6-4PPs. The kinetics of the p53-dependent
induction of XPC and p48 following UV parallel the
timeline of CPD repair and thus the primary function
of the inducible proteins maybe to replenish the lev-
els of repair factors following proteasome-mediated
degradation, to ensure maintenance of the lesion re-
pair process and to direct the slower kinetics of CPD
5. p53, BRCA1 and GGR
Several lines of evidence suggest that p53 and
BRCA1 share common mechanisms in their roles
S. Adimoolam, J.M. Ford/DNA Repair 2 (2003) 947–954
as tumor suppressor genes. Mutations in the p53
tumor suppressor gene are found in 70–80% of
BRCA1-mutated breast cancers but only in 30% of
BRCA1 wildtype breast tumors [48,49] implying that
loss of p53 function is required for the pathogenesis
of BRCA1-mutated tumors. In addition, homozygous
inactivation of BRCA1 in mice results in embryonic
lethality that is partially rescued by inactivation of
p53 . Furthermore, upon exposure to a variety of
DNA damaging agents, including doxorubicin, ion-
izing radiation and mitomycin C, protein expression
of BRCA1 is downregulated in p53 wildtype cells.
In contrast, BRCA1 is stabilized or upregulated after
DNA damage in p53−/−cells [51,52], suggesting
that the cellular consequence of loss of functional p53
may be compensated by upregulation or stabilization
Due to these parallels, we evaluated the effect
of overexpression of BRCA1 protein on GGR and
TCR in a human tumor cell line and determined if
this effect was p53-dependent. Overexpression of
BRCA1 significantly increased GGR, but not TCR of
UV-photoproducts in cells null or wildtype for p53
. In addition, we found that induction of BRCA1
results in the increased expression of the XPC, DDB2,
and GADD45 genes, the products of which are all
involved in the initial DNA damage recognition
processes, independent of p53. Therefore, p53 and
BRCA1 appear to act synergistically to regulate the
damage recognition process in GGR.
6. Open questions in the field
Although a requirement for p53 in GGR has been
well established by our laboratory [13,16,18] and
by others [14,17,19,20], there is still some debate
surrounding the potential role of p53 in TCR. Us-
ing ligation-mediated PCR to determine repair at the
single nucleotide resolution, Therrien and coworkers
showed that removal of UV-B induced CPD lesions
from both the transcribed and non-transcribed strand
of the p53 and c-jun genes was enhanced in the pres-
ence of functional p53 . However, this appears to
be a UV wavelength-specific effect, since their results
with the same methods using UV-C as the irradiation
source correlated with previously reported observa-
tions demonstrating a GGR-specific defect associated
with p53 deficiency . These observations suggest
a potential role for p53 in the base excision repair
(BER) of UVB-induced oxidative DNA damage (see
next section), although this hypothesis awaits experi-
Recent observations by Rubbi and Milner implicate
p53 as a chromatin accessibility factor in NER .
They reported data suggesting that UV-induced chro-
matin relaxation requires p53, and that the inhibition
of unscheduled DNA synthesis as well as chromatin
relaxation resulting from inhibition of p53 (through
microinjection of anti-p53 antibodies) can be compen-
sated for by histone hyperacetylation following tri-
chostatin A treatment. Although the results implicate
p53 as a direct participant in NER through chromatin
remodeling, such a model does not take into account
studies showing that the requirement for p53 in NER
can be bypassed by overexpression of p53 regulated
damage recognition factors . Therefore, perhaps
p53 regulates the remodeling of chromatin at the level
of transcription, maybe by controlling expression of
histone acetylases or potentially through p48 .
While regulation of chromatin structure is clearly
necessary for lesion accessibility by NER factors, it
remains unclear what role p53 plays directly in this
process, versus the role of associated transcription
factors and downstream products.
7. p53 and other excision repair pathways
Far less studied than the relationship between p53
and NER is the potential role of p53 in BER activity.
Several investigators have recently noted a deficiency
in BER in p53 mutant cells using both in vitro and in
vivo approaches, although the mechanism for this ef-
fect remains unclear . Initial studies using extracts
from cells to examine repair of apurinic/apyrimidinic
(AP)-sites on plasmids in vitro found that repair in-
corporation was lost from cells containing mutations
in the p53 core domain [58,59]. In vivo studies of
host-cell reactivation of a heat and acid treated plas-
mid (to induce AP sites) containing a reporter gene
co-transfected with various p53 constructs into a p53
null cell line demonstrated enhanced reporter expres-
sion with wildtype p53 but not mutant forms [60,61].
In contrast to p53-dependent NER, evidence sug-
gests that p53 may interact directly with the BER
S. Adimoolam, J.M. Ford/DNA Repair 2 (2003) 947–954
complex. For example, Zhou et al.  found that re-
combinant p53 protein stimulated an in vitro recon-
stituted BER assay, potentially by binding APE-1 and
regulating DNA polymerase ? (pol ?) loading onto
AP-sites. Studies by Smith and coworkers , on the
other hand, suggest that p53 may also regulate genes
involved in BER. For example, following treatment
with the base damaging alkylating agent MMS, p53
null cells exhibited slow BER, as measured in vivo
using an alkaline comet assay. In this experimental
system, pol ? protein levels correlated with wildtype
p53 status, though APE1 levels and activity were un-
affected. In fact, previous work has identified pol ?
as a DNA damage inducible gene , thus raising
the possibility that it is transcriptionally regulated by
p53. Therefore, the few studies to date looking at the
Fig. 1. Model depicting p53-dependent NER. Upon DNA damage, p53 gets activated and, with the help of the p300/CBP coactivator
complexes, initiates transcription of XPC and DDB2 by binding to p53 response elements in their respective promoters. XPC binds 6-4PPs
directly and binding to CPDs potentially requires preliminary binding of p48, which is followed by proteasomal degradation of p48,
potentially to allow XPC to access the lesions. Initial damage recognition, particularly 6-4PP repair, most likely requires the basal levels
of these factors, whereas, since the kinetics of XPC and p48 induction parallel that of CPD repair, the inducible levels of these repair
proteins are probably required for CPD repair.
role for p53 in BER provide provocative evidence,
though the mechanism for this effect clearly remains
to be determined. Further detailed studies are needed
to delineate this relationship and explore mechanistic
possibilities for p53 regulation of BER activity and its
impact on p53-dependent NER, particularly following
irradiation with UV wavelengths that result in both
pyrimidine dimers and oxidative base damage.
A number of investigations have contributed to our
understanding of the ways in which loss of p53 ac-
tivity promotes mutagenesis and genomic instability.
Recent observations on the role of p53 in NER signify
S. Adimoolam, J.M. Ford/DNA Repair 2 (2003) 947–954
that mutations in p53 may lead to increased genomic
instability due to a reduced efficiency of DNA repair,
in addition to alterations in DNA damage induced
cell cycle checkpoints and apoptosis. Hence, under-
standing the mechanism governing the role of p53 in
DNA repair is of paramount importance. We now have
novel insights into the molecular mechanisms of the
p53-dependent regulation of NER. Similar to its in-
volvement in the regulation of cell cycle checkpoints
and apoptosis, p53 acts as a transcription factor to reg-
nition process of the p53-dependent NER pathway, as
depicted in Fig. 1. In response to DNA damage, p53
is induced and activated, which in turn transcription-
ally regulates expression of the GGR-specific dam-
age recognition factors, p48 and XPC. The timeline of
events during the initial steps of GGR are suggestive
that the basal levels of these enzymes are sufficient for
6-4PP repair, whereas both the basal and induced pro-
teins are required for CPD repair. These studies further
our understanding on the important roles of p53 and
p53-regulated genes in NER. The list of p53-induced
genes being identified is steadily rising, which may
further pave the way for the identification of other
known or novel p53-regulated genes in NER.
S.A. was supported by the American Cancer So-
ciety Postdoctoral Fellowship PF-0122901-MGO.
J.M.F. was supported by the National Institutes of
Health Award RO1 CA83889, a Sidney Kimmel
Foundation for Cancer Research Scholar Award, and
a Burroughs Wellcome Fund New Investigator Award
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