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A concise review of DNA damage checkpoints and repair in mammalian cells


Abstract and Figures

DNA of eukaryotic cells, including vascular cells, is under the constant attack of chemicals, free radicals, or ionizing radiation that can be caused by environmental exposure, by-products of intracellular metabolism, or medical therapy. Damage may be either limited to altered DNA bases and abasic sites or extensive like double-strand breaks (DSBs). Nuclear proteins sense this damage and initiate the attachment of protein complexes at the site of the lesion. Subsequently, signal transducers, mediators, and finally, effector proteins phosphorylate targets (e.g., p53) that eventually results in cell cycle arrest at the G1/S, intra-S, or G2/M checkpoint until the lesion undergoes repair. Defective cell cycle arrest at the respective checkpoints is associated with genome instability and oncogenesis. When cell cycle arrest is accomplished, the DNA repair machinery can become effective. Important pathways in mammalian cells are the following: base excision repair, nucleotide excision repair, mismatch repair, and DSB repair. When repair is successful, the cell cycle arrest may be lifted. If repair is unsuccessful (e.g., by high doses of DNA-damaging agents or genetic defects in the DNA repair machinery), then this may lead to permanent cell cycle arrest (cellular senescence), apoptosis, or oncogenesis.
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A concise review of DNA damage checkpoints and repair in
mammalian cells
Jaco H. Houtgraaf
, Jorie Versmissen
, Wim J. van der Giessen
Department of Cell Biology and Genetics, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
Department of Cardiology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
Received 12 January 2006; accepted 6 February 2006
Abstract DNA of eukaryotic cells, including vascular cells, is under the constant attack of chemicals, free
radicals, or ionizing radiation that can be caused by environmental exposure, by-products of
intracellular metabolism, or medical therapy. Damage may be either limited to altered DNA bases
and abasic sites or extensive like double-strand breaks (DSBs). Nuclear proteins sense this damage
and initiate the attachment of protein complexes at the site of the lesion. Subsequently, signal
transducers, mediators, and finally, effector proteins phosphorylate targets (e.g., p53) that eventually
results in cell cycle arrest at the G1/S, intra-S, or G2/M checkpoint until the lesion undergoes repair.
Defective cell cycle arrest at the respective checkpoints is associated with genome instability and
oncogenesis. When cell cycle arrest is accomplished, the DNA repair machinery can become
effective. Important pathways in mammalian cells are the following: base excision repair, nucleotide
excision repair, mismatch repair, and DSB repair. When repair is successful, the cell cycle arrest may
be lifted. If repair is unsuccessful (e.g., by high doses of DNA-damaging agents or genetic defects in
the DNA repair machinery), then this may lead to permanent cell cycle arrest (cellular senescence),
apoptosis, or oncogenesis.
D2006 Elsevier Inc. All rights reserved.
Keywords: DNA damage checkpoints; Repair; Nuclear proteins; Cell cycle
1. Introduction
The genome of eukaryotic cells is under constant attack.
A wide diversity of lesions caused by environmental agents
such as ultraviolet (UV) radiation in sunlight, ionizing
radiation, and numerous genotoxic chemicals can arise in
the DNA. In addition, the genome is also threatened from
within. By-products of normal cellular metabolism, such as
reactive oxygen species (ROS; i.e., superoxide anions,
hydroxyl radicals, and hydrogen peroxide) derived from
oxidative respiration and products of lipid peroxidation, can
cause a variety of damages in the DNA (Fig. 1).
On the other hand, DNA-damaging agents such as
ionizing radiation, UV light (photodynamic therapy), and
most chemotherapeutic agents are increasingly being used to
treat common disorders like arterial (re)stenosis (brachy-
therapy and drug-eluting stents) or cancer.
Whereas DNA damage in terminally differentiated cells
(such as muscle cells) gives rise to DNA damage repair to
ensure the integrity of the transcribed genome, the induction
of DNA damage in dividing cells results in the activation of
cell cycle checkpoints. These checkpoints halt the prolifer-
ating cell in its cell cycle progression in order to give time to
the DNA damage repair machinery to do its work, thereby
avoiding incorrect genetic information from being passed
1553-8389/06/$ – see front matter D2006 Elsevier Inc. All rights reserved.
4Corresponding author. Tel.: +31 104635245.
E-mail address: (W.J. van der Giessen).
Funded by Netherlands Heart Foundation Grant No. 99118.
Cardiovascular Revascularization Medicine 7 (2006) 165 – 172
onto the progeny. Especially when mutations are accumu-
lating, the chance of developing uncontrolled cell growth
(oncogenesis) is substantial. A variety of lesions can occur
in the DNA, including single- and double-strand breaks
(DSBs), mismatches, and chemical adducts. Therefore,
multiple repair pathways have evolved, each directed to a
specific type of lesion. Each pathway consists of numerous
proteins forming a cascade in order to repair the damage as
accurate as possible.
Eventually, when the repair process fails, the cell cycle
can be blocked permanently, leading to a senescent state of
the cell, or alternatively, apoptosis may be induced. Both
mechanisms prevent potentially harmful cells from dividing,
ensuring that no mutations are inherited by the next
generation of cells.
2. Cell cycle checkpoints
The cell cycle in eukaryotic cells consists of four
phases, gap (G)1, synthesis (S), G2, and mitosis (M), and
one phase outside the cell cycle, G
(Fig. 2). In the G1
phase, directly after mitosis, the cell increases in size and
starts synthesizing RNA (transcription) and proteins (trans-
lation). In the subsequent S phase, DNA is replicated to
produce an exact copy of the genome for the subsequent
daughter cells. During G2, the cell will grow and make
extra proteins to ensure that two viable daughter cells can
be formed. RNA and protein syntheses that started in the
G1 phase are continued during the S and G2 phases.
Finally, the cell will go into the M phase. In this phase, the
chromosomes are organized in such a way that two
genetically identical daughter cells can be produced, after
which the whole cycle can start again. Cells can also stop
dividing and remain in G
. They may stay in this state for
hours, days, weeks, or even years before they start
dividing again or even stay in G
permanently until the
organism dies.
In a normal cell cycle, the passage from one stage to
another is thoroughly controlled. Although still under
debate, genetic evidence that proteins involved in the
orderly progression through the cell cycle are also involved
in the checkpoint response to DNA damage is accumulating.
This implies that in all cells, these cell cycle checkpoint
intrastrand CROSS-LINKS
Fig. 1. Summary of the most common types of DNA lesions that can be caused by exogenous or endogenous damaging agents. They may affect a single strand
or both strands of the DNA. The assumed repair pathway that operates on the various lesions is also indicated.
Fig. 2. Schematic representation of the cell cycle. DNA damage triggers
activation of these cell cycle checkpoints, which can lead to an arrest at the
G1/S, intra-S, or G2/M phase (indicated in red). During cell cycle arrest, the
DNA damage can be repaired.
J.H. Houtgraaf et al. / Cardiovascular Revascularization Medicine 7 (2006) 165 – 172166
pathways are active, but they are up-regulated when DNA
damage occurs.
The cell cycle checkpoint pathways mentioned above are
operational during the entire cell cycle and, hence, may slow
down the cell cycle at any point during the four phases, but
the term checkpoint is defined more upon the transition
between phases, which is being inhibited by DNA damage
at the G1/S, intra-S, and G2/M checkpoints. Although these
checkpoints are distinct, they all respond to DNA damage
and share many proteins. The intra-S-phase checkpoint
differs from the G1/S and G2/M checkpoints since it also
has to recognize and deal with replication intermediates and
stalled replication forks. Also, in the S phase, another
checkpoint that prevents transmission of unreplicated DNA
is active. This process inhibits mitosis while DNA
replication is ongoing or blocked. The signal for this
checkpoint is unreplicated DNA rather than DNA damage.
The DNA damage response during any phase of the cell
cycle has the same pattern. After the detection of DNA
damage by sensor proteins, signal transducer proteins
transduce the signal to effector proteins. These effector
proteins launch a cascade of events that causes cell cycle
arrest, apoptosis, DNA repair, and/or activation of damage-
induced transcription programs (Fig. 3).
2.1. Damage sensors and signal transducers
Although the sensors required for DNA repair are partly
known, the sensors that eventually lead to cell cycle arrest
are largely unknown. Different types of DNA lesions, as
well as very low levels of damage, have to be recognized.
The lesion itself can be recognized, but it is also possible
that the damage covered by a complex of repair proteins
forms the signal for checkpoint reactions or even inter-
mediates formed during repair. The exact mechanism, as
mentioned before, is still not completely resolved.
The first group that has been found to function as a
sensor consists of proliferating cell nuclear antigen (PCNA)-
like and replication factor C (RFC)-like protein complexes
(Fig. 4). The candidate DNA damage sensors Rad9, Hus1,
and Rad1 form a ring structure (the b9–1–1Qcomplex) that
can encircle the DNA similar to PCNA. Since it has a ring
structure, this complex has to be loaded on the DNA by a
clamp loader. Whereas, during replication, PCNA is loaded
on the DNA by RFC, which consists of five subunits
), the 9–1–1 complex is loaded on damaged DNA
by a protein complex that consists of four RFC (RFC
subunits and Rad17, forming the Rad17–RFC
As soon as the 9–1–1 complex is bound to the damaged
DNA, it is expected to form a scaffold for downstream
checkpoint and repair proteins.
Another group of important players in the early response
to DNA damage consists of ataxia telangiectasa (AT) mu-
tated (ATM) and ATM and Rad3 related (ATR). AT, caused
by mutated ATM, is an autosomal recessive disorder,
characterized by immunodeficiency, neurological disorders,
and high cancer susceptibility. ATR was identified later on
basis of sequence and functional homology to ATM.
Whereas patients, mice, and cells without active ATM are
viable, the complete absence of ATR leads to embryonic
lethality. This suggests (and evidence is accumulating) that
ATR also functions in essential cellular processes in
undamaged cells like DNA replication and cellular differ-
entiation. The ATM and ATR proteins belong to the
Fig. 3. Flowchart of the cellular response to any kind of DNA damage. In proliferating cells, cell cycle checkpoints will be activated, leading to a cell cycle
arrest and providing time to the activated DNA damage repair machinery to repair the DNA damage. In resting/terminally differentiated cells, DNA repair will
be initiated directly. When repair is complete, the cell may proceed in its cell cycle. If the damage cannot be repaired or if there is too much damage for the
DNA repair machinery to overcome, then the cell cycle can be blocked permanently, leading to a senescent state of the cell, or apoptosis may be induced. If
unrepaired damages remain undetected, then this may lead to mutations and genomic instability that ultimately can lead to oncogenesis.
J.H. Houtgraaf et al. / Cardiovascular Revascularization Medicine 7 (2006) 165 – 172 167
phosphatidylinositol 3-kinase-like (PIKK) family of serine/
threonine protein kinases. This family also includes DNA-
PK, an enzyme that is involved in repair of DSBs during
nonhomologous end joining (NHEJ; Fig. 5D).
ATM appears to be the primary player in response
to ionizing radiation. Recent results suggest that the Rad50/
Mre11/Nijmegen Breakage Syndrome 1 (NBS1) complex
functions as the DSB sensor for ATM but is in turn also
a downstream target. ATR is more important in response
to UV, MMS, and replication inhibitors such as hydroxy-
urea (HU).
The Rad50/Mre11/NBS1 complex, ATM and ATR, the
previously described Rad17/RFC
, and the 9–1–1 com-
plex localize to sites of DNA damage independently but
interact to trigger the checkpoint-signaling cascade. For
example, ATR and ATM phosphorylate Rad17. Increased
amounts of 9–1–1 complexes, which are recruited by Rad17
to DNA damage sites, stimulate this phosphorylation. It is
not yet known how Rad17 phosphorylation contributes to
the checkpoint pathway. On the other hand, mammalian
Rad17 and HUS1 are required for the phosphorylation of
Check (Chk)1 by ATR. Therefore, next to the expected
sensor function, Rad17 and the 9–1–1 complex play a role
in the facilitation of signal transduction and, possibly, in the
amplification of the damage signal. ATM and ATR carry out
the actual signal transduction to the effector kinases Chk1
and Chk2.
2.2. Mediators
In addition to damage sensors, signal transducers, and
effector proteins, many other proteins are involved in the
DNA damage response. They are mostly cell cycle specific
and associate with damage sensors, signal transducers, and
effectors at particular phases of the cell cycle and, as a
consequence, help provide signal transduction specificity.
ATM and ATR phosphorylate most of these mediators. Well-
known examples of mediators are p53 binding protein
(53bp), the topoisomerase binding protein TopBP1, and
mediator of DNA damage checkpoint (MDC1). Next to these
mediators, many proteins fulfilling other functions have
additional functions in checkpoint pathways. Examples of
these are BRCA1 and the earlier mentioned Rad50/Mre11/
NBS1 complex, which are also involved in DNA repair.
2.3. Effector proteins: Chk1 and Chk2
Chk1 and Chk2 are, like ATM and ATR, serine/threonine
protein kinases and phosphorylate targets that eventually
result in the cell cycle arrest. In mammalian cells, both
kinases play a role in all checkpoint pathways responsive to
DNA damage. The DSB signal sensed by ATM is
transduced by Chk2, and the UV damage signal sensed by
ATR is transduced by Chk1, although there is some overlap
and redundancy between the functions of these two proteins.
Chk1 and Chk2 transfer the signal of DNA damage to the
phosphotyrosine phosphatases and cell division cycle
proteins Cdc25A, Cdc25B, and Cdc25C. Phosphorylation
of Cdc25A–C by Chk1 or Chk2 inactivates Cdc25A–C,
whereas unphosphorylated Cdc25A–C promotes the G1/S
and G2/M transition by dephosphorylating the cyclin-
dependent kinases (CDKs) directly involved in cell cycle
transition. However, there are some differences between the
different checkpoints, which will be discussed below.
2.4. G1/S checkpoint
Nonphosphorylated Cdc25A protein promotes the G1/S
transition (by dephosphorylation of CDK2, which phos-
phorylates Cdc45 that is involved in initiating replication).
The exact pathway of cell cycle arrest depends on the
kind of damage. DNA DSBs lead to phosphorylation of
ATM that subsequently phosphorylates Chk2. Single-strand
gaps result in the activation of Rad17–RFC, the 9–1–1
Fig. 4. Simplified representation of the DNA-damage-induced checkpoint
response. After the detection of a given damage by sensor proteins, this
signal is transduced to the effector proteins Chk1 and Chk2 via the
transducer proteins ATR and ATM. Depending on the phase of the cell
cycle the cell is in, this can lead to activation of p53 and inactivation of
CDC25, which eventually leads to cell cycle arrest. Mediator proteins
mostly are cell cycle specific and associate with damage sensors, signal
transducers, or effectors at particular phases of the cell cycle and, thus, help
provide signal transduction specificity.
J.H. Houtgraaf et al. / Cardiovascular Revascularization Medicine 7 (2006) 165 – 172168
complex, and ATR, which leads to phosphorylation of
Chk1. Subsequent phosphorylation of Cdc25A by Chk1 or
Chk2 causes inactivation of this protein by nuclear
exclusion and ubiquitin-mediated proteolytic degradation,
leading to G1 arrest. ATM and ATR also phosphorylate p53,
which leads to stabilization and accumulation of the p53
protein and promotes the transcription factor activity of p53.
The target of the transcription factor p53 is p21, which, in
turn, inhibits CDK2 activity, causing maintenance of arrest
of the cell cycle.
2.5. Intra-S-phase checkpoint
Two pathways mediate the intra-S-phase checkpoint.
Firstly, the ATM/ATR–Chk2/Chk1–Cdc25A–CDK2 path-
way is more or less similar to the G1/S checkpoint. In the
S phase, this pathway delays replication (by blocking the
loading of Cdc45 onto chromatin that in turn attracts DNA
polymerase-ainto prereplication complexes) and, as a
consequence, extends the DNA replication time, allowing
DNA repair to take place. The second pathway involves
NBS1 (a human disorder characterized by cancer predis-
position, immunodeficiency, hypersensitivity to ionizing
radiation, chromosomal instability, and growth retardation),
which is phosphorylated by ATM together with Chk2,
leading to a cascade involving also Mre11- and Rad50-like
initial DSB recognition, which plays a role not only in cell
cycle arrest but also in activating the repair processes.
2.6. G2/M checkpoint
When cells encounter DNA damage in G2, the G2/M
checkpoint stops the cell cycle in order to prevent the cell
from entering mitosis. As in the G1/S checkpoint, the kind
of DNA damage determines the pathway that will be
activated: ATM–Chk2–Cdc25 for DSBs and ATR–Chk1–
Cdc25 for DNA lesions such as those created by UV light.
Besides down-regulating Cdc25A, both Chk1 and Chk2 up-
regulate WEE1 by phosphorylation, which together control
Cdc2/CyclinB activity. This latter complex promotes G2/M
transition under normal circumstances, and inactivation
blocks the cell cycle when damage occurs in G2. The
maintenance of this arrest seems to be partly p53/p21
independent unlike the G1/S checkpoint, whereas tumor
cells lacking functional p53 still tend to accumulate in G2
after induction of DNA damage.
As the cell cycle checkpoint pathways are predominantly
evolved to prevent transducing DNA damage to daughter
cells, it is obvious that defects in checkpoint responses can
result in genomic instability, leading to the transformation of
normal cells into cancer cells. Indeed, absence of ATM or
p53 causes syndromes featuring cancer susceptibility. In
addition, other genes involved in cell cycle checkpoints are
related to cancer, most of them also having a function in
DNA repair. This combination probably makes mutations or
deletions more severe: less repair and less control.
3. DNA damage repair
DNA damage checkpoints can only prevent the trans-
duction of mutations to daughter cells by means of an
efficient DNA damage repair machinery. As there are many
different lesions possible, different types of repair pathways
have evolved. Important pathways in mammalian cells
include base excision repair (BER), nucleotide excision
repair (NER), mismatch repair (MMR), and DSB repair
(Fig. 5A–D).
3.1. Base excision repair
BER is the main guardian against damage due to cellular
metabolism. Inactivation of the BER core proteins in mice
leads to embryonic lethality, highlighting the importance of
this pathway. Base damages are generated by ROS, ionizing
radiation, and indirectly also by UV radiation (via gen-
eration of ROS) or can be the result of various chemicals
like chemotherapeutic drugs (e.g., adriamycin, mitomycin
C, and psoralen). In BER, the damaged base is removed by
different DNA glycosylases (depending on the damage) and
APE1 endonuclease (Fig. 5A). This results in an abasic site,
from which both ends are trimmed by poly(ADP-ribose)
polymerase and polynucleotide kinase to facilitate repair
synthesis. In mammals, the so-called short-patch repair is
the dominant mode for the remainder of the reaction. The
single-stranded, one-nucleotide gap is filled in by DNA
polymerase-hand subsequently ligated by the Ligase3/
XRCC1 complex. The long-patch repair mode involves
DNA polymerase-h, DNA polymerase-ba¨/a
˚,Qand PCNA for
repair synthesis, as well as the FEN1 endonuclease to
remove the displaced DNA flap and DNA ligase1 for
sealing the backbone of the DNA double helix.
3.2. Nucleotide excision repair
NER is the most important repair system to remove
bulky DNA lesions that can be caused by UV radiation
(thymidine dimers), chemicals, or ROS. In NER, there are
two modes of activation of the pathway (Fig. 5B). The
global genome NER pathway scans the genome constantly
and recognizes the damage caused by XPC [named after
one of the seven genes (XPA to XPG) involved in this
pathway, the disruption of which causes the UV-sensitive
and skin-cancer-prone (N1000-fold incidence) disorder
xeroderma pigmentosum in humans]. The second mode
of activation occurs when RNA polymerase II is blocked
by a damage during transcription. This stalled polymerase
must be displaced to make the damage accessible for
repair, which requires at least two transcription-coupled
repair proteins: CS-A and CS-B (for Cockayne syndrome,
another rare UV-sensitive disorder in humans). After the
recognition step, both pathways are identical. The DNA
duplex is unwound by the multi-subunit transcription
factor Transcription Factor IIH that contains the two
J.H. Houtgraaf et al. / Cardiovascular Revascularization Medicine 7 (2006) 165 – 172 169
DNA pol-β, Pol-δ/ε
Ligase III
Ligase I
ADNA polymerase-α
Exonuclease (3’- 5’)
DNA polymerase-δ/ε
DNA polymerase-α
Fig. 5. DNA repair mechanisms. (A) BER: Damage repaired by BER may be caused by ionizing radiation, alkalyting agents, and oxygen radicals. These agents cause single-strand breaks or small alteration of
bases. The mechanism of repair through BER is shown in the figure and explained in the text. (B) NER: Damage that distorts the normal architecture of the DNA helix is repaired through NER. This type of
damage can be caused by UV light, cisplatin, and other chemotherapeutic drugs. Disruption of the DNA helix interferes with base pairing and obstructs transcription and normal replication. The mechanism of
repair through NER is shown in the figure and explained in the text. (C) MMR: Errors occurring during DNA replication can cause base mismatches or small insertions or deletions of nucleotides. These errors are
removed by MMR. A model for MMR is shown in the figure and explained in the text. (D) DSB repair: DNA DSBs can be repaired by at least two mechanically distinct pathways: HR and NHEJ. This figure
shows a simplification of both models for DSB repair. During HR, the damaged DNA (gray) uses the sister chromatid or homologous chromosome (red) as a template to repair the DNA accurately. NHEJ repairs
the DNA by simply joining the DNA ends in a way that is not necessarily error free, since no template is used for the newly synthesized DNA at the damaged sites (red). A number of proteins involved in each
pathway are indicated and discussed in the text.
J.H. Houtgraaf et al. / Cardiovascular Revascularization Medicine 7 (2006) 165 – 172170
helicases XPB and XPD. During this process, XPA
confirms the presence of DNA damage, and when one is
not detected, it aborts NER. Subsequently, a more stable
preincision complex is formed with the aid of Replication
Protein A. Finally, XPG cleaves the damaged strand 3Vof
the damage, and the XPF/ERCC1 complex cleaves the
same strand 5Vof the lesion, generating a 24- or 32-base
oligonucleotide fragment containing the injury. The single-
strand gap that remains is filled in by DNA polymerase-y/q
with the aid of the replication accessory protein PCNA
(regular DNA replication machinery).
3.3. Mismatch repair
Replication errors by DNA polymerase-aor -ba¨/a
(regular replication machinery) can result in mismatched
bases (A–G or C–T). The MMR process begins with the
proteins Msh2–6 that recognize and bind to the mismatched
base pairs (Fig. 5C). Then, Mlh1 and Pms2 are recruited to
the complex. Subsequently, the mismatched strands are
cleaved, and the segment from the cleavage site to the
mismatch is removed by an exonuclease. DNA polymerase-
afills in the single-strand gap.
Rad51, Rad52, Rad54
Rad50, Mre11, Nbs1
Brca1, Brca2
Ku70, Ku80, DNA-PKcs
Ligase IV, Xrcc4
Fig. 5 (continued )
J.H. Houtgraaf et al. / Cardiovascular Revascularization Medicine 7 (2006) 165 – 172 171
3.4. DSB repair
DSBs are a very genotoxic type of DNA damage.
Because both strands of the DNA double helix are broken,
chromosomal fragmentation, translocation, and deletions
can easily occur and rapid repair is crucial. DNA DSBs
can be caused by ionizing radiation, ROS, and chemo-
therapeutic drugs and can arise during replication of a
single-strand break.
In recent studies, it was shown that one of the first
responses of eukaryotic cells to DSBs is the extensive
phosphorylation of a member of the histone H2A family,
H2AX (g-H2AX), by ATM and other PI3-like kinases.
Phosphorylation already occurs within 1–3 min after
induction of DNA damage. The exact reason of this
phenomenon is not yet clarified, although a role in DNA
damage repair and chromosomal stability is evident.
In order to repair DNA DSBs, two distinct pathways
have evolved: homologous recombination (HR) and NHEJ
(Fig. 5D). The two main differences between these
pathways are the requirement for extensive DNA homol-
ogy on the sister chromatid in HR and the accuracy of
repair. HR is mediated by the Rad52 epistasis group that
includes the Rad51, Rad52, and Rad54 genes. After
introduction of the DSB, Rad51, which is the central
protein in HR, searches the genome for an intact copy of
the broken DNA on the sister chromatid. After this, the
missing information on the broken strand is copied in, and
the damage is repaired without loss of genetic information.
In NHEJ, on the contrary, there is no need for homology.
The two ends of the broken double helix are directly
ligated together by the DNA ligaseIV/Xrcc4 complex.
Other proteins involved in this pathway are the Ku70/80
heterodimer, DNA-PK
, and the Rad50/Mre11/NBS1
complex. NHEJ is less accurate and might give rise
to deletions.
Although both DSB repair pathways are operational in
mammals, their relative contribution might differ depending
on the stage of the cell cycle or the cell type. For HR to
occur, there is a need for a sister chromatid, which is not
produced until the S phase. For this reason, HR can only
take place in dividing cells that are in the S or G2 phase.
Cells in G
and G1 or terminally differentiated cells will
have to rely on NHEJ.
A number of the previously mentioned DNA DSB repair
proteins (for instance, Rad51, Rad54, and the MRN
complex) and g-H2AX relocate into bright nuclear foci
after induction of DNA damage (Fig. 6). These foci are
believed to play an important role as DNA damage repair
factories, harboring thousands of repair and cell cycle
checkpoint proteins, although their exact role remains to
be elucidated.
4. Concluding remarks
Over the past 30 years, our knowledge about DNA
damage, DNA damage checkpoints, and DNA repair
has increased dramatically. This brief review should be
regarded as an introduction to the knowledge accumulated
over those years. It should be emphasized that many issues
remain unsolved yet. However, the concept of DNA damage
and repair is very important for our understanding of the
pathogenesis and treatment of many disease processes.
We would like to thank Dr L.R. van Veelen for kindly
providing (Figs. 2, 3, and 5) and A.K. Dik for valuable help
with the other figures. Also, we would like to thank V. Smits
and J. Essers for carefully reading the manuscript.
Fig. 6. Ionizing-radiation-induced foci. Immunohistochemical staining for Rad51 (protein involved in HR) in a vascular smooth muscle cell before and 8 h after
irradiation with 12 Gy of g-radiation. Clearly visible are the bright nuclear foci appearing, which are believed to be bDNA damage repair factoriesQin which
accumulation of many of the proteins discussed in this review (i.e., g-H2AX, Rad54, Rad52, and MRN complex) takes place.
J.H. Houtgraaf et al. / Cardiovascular Revascularization Medicine 7 (2006) 165 – 172172
... La plupart des focis sont réparés dans les 24 h suivant l'irradiation . L'immunofluorescence permet de quantifier et détecter la localisation nucléaire des protéines γH2AX suite à une irradiation allant de 1 mGy à 10 Gy (Joubert & Foray, 2007 (Houtgraaf et al., 2006;Joubert & Foray, 2007;Viau et al., 2016). ...
... Le processus de NER est le plus polyvalent en termes de réparation à l'ADN. Il existe 2 mécanismes de NER : la NER globale du génome (GG-NER, Global genome NER) qui est utilisée suite aux dommages radio-induits par les UV et la réparation couplée à la transcription (TCP, Transcription Coupled Repair) qui assure la réparation des dommages aux UV et au stress oxydatif (Hoeijmakers, 2001;Houtgraaf et al., 2006). Ce dernier mécanisme est activé lorsque l'ADN polymérase II est bloqué au moment de la transcription ce qui entraîne le recrutement de plus de 25 protéines pour restaurer le brin d'ADN (Hoeijmakers, 2001 (Hoeijmakers, 2001). ...
Malgré l’évolution de la radiothérapie (RT), la toxicité aux tissus sains reste une limite en clinique. Les mesures d’Efficacité Biologique Relative (EBR) permettent de prédire les effets biologiques d’un rayonnement d’intérêt par rapport à celui de référence. Elles sont principalement basées sur le test de survie clonogénique qui ne peut suffire à lui seul à prédire le devenir de tissus sains exposés. Les nouveaux appareils de RT utilisent des débits de dose plus élevés sans que les effets biologiques soient bien connus. Le but de ces travaux est d’acquérir des mesures biologiques multiparamétriques à intégrer dans un futur modèle prédictif pour mieux prédire les effets biologiques des protocoles de RT émergents. Pour les irradiations (IR) en dose unique, la modélisation des données in vitro a mis en évidence un effet plus délétère du débit de dose le plus élevé sur la survie clonogénique, la morphologie, la viabilité et le cycle cellulaire, la sénescence et l’expression de gènes signant une dysfonction cellulaire. Ces résultats ont été confirmés in vivo sur un modèle d’IR intestinale. Contrairement au postulat de la CIPR, l’EBR des photons n’est pas de 1 et dépend du débit de dose. Pour les IR fractionnées selon différents protocoles, un impact du débit de dose sur un continuum de “dose biologique équivalente” (BED) a également été démontré in vitro. En revanche, la réponse in vitro et in vivo est différente pour des protocoles à BED équivalente ce qui montre une limite son utilisation pour comparer des protocoles. L’utilisation de mesures biologiques multiples pourrait permettre à terme de mieux prédire les risques potentiels des pratiques actuelles et futures en RT.
... The cell cycle consists offour phases: G1, S, G2 and M. Cells have a strict cell cycle checkpoint mechanism to ensure the correct transmission of genetic materials to the next generation of cells. Dysfunction in checkpoints can lead to abnormal proliferation of cells and tumorigenesis (70). Under normal circumstances, in the case of DNA damage, the ATR-CHK1-CDC25 pathway may be activated to inhibit cyclinA/B-CDK1 complex and hence block the cell replication arresting at G2 phase (71). ...
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Despite a generally better prognosis than high-grade glioma (HGG), recurrence and malignant progression are the main causes for the poor prognosis and difficulties in the treatment of low-grade glioma (LGG). It is of great importance to learn about the risk factors and underlying mechanisms of LGG recurrence and progression. In this study, the transcriptome characteristics of four groups, namely, normal brain tissue and recurrent LGG (rLGG), normal brain tissue and secondary glioblastoma (sGBM), primary LGG (pLGG) and rLGG, and pLGG and sGBM, were compared using Chinese Glioma Genome Atlas (CGGA) and Genotype-Tissue Expression Project (GTEx) databases. In this study, 296 downregulated and 396 upregulated differentially expressed genes (DEGs) with high consensus were screened out. Univariate Cox regression analysis of data from The Cancer Genome Atlas (TCGA) yielded 86 prognostically relevant DEGs; a prognostic prediction model based on five key genes (HOXA1, KIF18A, FAM133A, HGF, and MN1) was established using the least absolute shrinkage and selection operator (LASSO) regression dimensionality reduction and multivariate Cox regression analysis. LGG was divided into high- and low-risk groups using this prediction model. Gene Set Enrichment Analysis (GSEA) revealed that signaling pathway differences in the high- and low-risk groups were mainly seen in tumor immune regulation and DNA damage-related cell cycle checkpoints. Furthermore, the infiltration of immune cells in the high- and low-risk groups was analyzed, which indicated a stronger infiltration of immune cells in the high-risk group than that in the low-risk group, suggesting that an immune microenvironment more conducive to tumor growth emerged due to the interaction between tumor and immune cells. The tumor mutational burden and tumor methylation burden in the high- and low-risk groups were also analyzed, which indicated higher gene mutation burden and lower DNA methylation level in the high-risk group, suggesting that with the accumulation of genomic mutations and epigenetic changes, tumor cells continued to evolve and led to the progression of LGG to HGG. Finally, the value of potential therapeutic targets for the five key genes was analyzed, and findings demonstrated that KIF18A was the gene most likely to be a potential therapeutic target. In conclusion, the prediction model based on these five key genes can better identify the high- and low-risk groups of LGG and lay a solid foundation for evaluating the risk of LGG recurrence and malignant progression.
... This is obvious by G2/M arrest, as evident by the greater percentage of cells in the G2/M phase (100 and 200 µM) to fix the damage. However, the transient G2/M arrest was not a permanent and the cells arrested in the SubG1 apoptotic phase (100, 200, 400 µM), clearly indicating a solid reason to recognize the unsuccessful repair of DNA [49]. Similar to our data, TCP-, TECP-, and TDCPP-exposed cell lines have shown DNA damage [29,47,50]. ...
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Tris (2-ethylhexyl) phosphate (TEHP) is an organophosphate flame retardant (OPFRs) which is extensively used as a plasticizer and has been detected in human body fluids. Contemporarily, toxicological studies on TEHP in human cells are very limited and there are few studies on its genotoxicity and cell death mechanism in human liver cells (HepG2). Herein, we find that HepG2 cells exposed to TEHP (100, 200, 400 µM) for 72 h reduced cell survival to 19.68%, 49.83%, 58.91% and 29.08%, 47.7% and 57.90%, measured by MTT and NRU assays. TEHP did not induce cytotoxicity at lower concentrations (5, 10, 25, 50 µM) after 24 h and 48 h of exposure. Flow cytometric analysis of TEHP-treated cells elevated intracellular reactive oxygen species (ROS), nitric oxide (NO), Ca++ influx and esterase levels, leading to mitochondrial dysfunction (ΔΨm). DNA damage analysis by comet assay showed 4.67, 9.35, 13.78-fold greater OTM values in TEHP (100, 200, 400 µM)-treated cells. Cell cycle analysis exhibited 23.1%, 29.6%, and 50.8% of cells in SubG1 apoptotic phase after TEHP (100, 200 and 400 μM) treatment. Immunofluorescence data affirmed the activation of P53, caspase 3 and 9 proteins in TEHP-treated cells. In qPCR array of 84 genes, HepG2 cells treated with TEHP (100 µM, 72 h) upregulated 10 genes and downregulated 4 genes belonging to a human cancer pathway. Our novel data categorically indicate that TEHP is an oxidative stressor and carcinogenic entity, which exaggerates mitochondrial functions to induce cyto- and genotoxicity and cell death, implying its hepatotoxic features.
... Once DNA damage is detected, cell cycle arrest and DNA repair machinery are initiated. If the cell incurs substantial, unrepaired DNA damage, apoptosis is initiated [30][31][32]. Any combination of treatments that overwhelm DDR machinery by causing excessive DNA damage, impaired DNA repair, or both, could provide a valuable therapeutic option. ...
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Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)—enzalutamide and abiraterone—have been the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, responses to the second NAA are infrequent (25–30%) and short-lasting (median PFS ~3 months). With the growing adoption of NAA therapy in pre-metastatic castration-resistant settings, finding better treatment options for first-line mCRPC has become an urgent clinical need. The regulatory approval of two PARP inhibitors in 2020—rucaparib and olaparib—has provided the first targeted therapy option for patients harboring defects in selected DNA damage response and repair (DDR) pathway genes. However, a growing body of preclinical and clinical data shows that co-inhibition of AR and PARP induces synthetic lethality and could be a promising therapy for patients without any DDR alterations. In this review article, we will investigate the limitations of NAA monotherapy, the mechanistic rationale for synthetic lethality induced by co-inhibition of AR and PARP, the clinical data that have led to the global development of a number of these AR and PARP combination therapies, and how this may impact patient care in the next 2–10 years.
... These regulatory proteins and catalytic enzymes could be cited as cyclins (A, B, D, E, and H), and cyclindependent-kinases (1, 2, 4, 6, or 7). The cyclins are a family of proteins that function as regulatory subunits for cyclindependent-kinases (CDKs) [14][15][16]. ...
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Background Cancer refers to a group of some of the worldwide most diagnosed and deadliest pathophysiological conditions that conquered researchers’ attention for decades and yet begs for more questions for a full comprehension of its complex cellular and molecular pathology. Main body The disease conditions are commonly characterized by unrestricted cell proliferation and dysfunctional replicative senescence pathways. In fact, the cell cycle operates under the rigorous control of complex signaling pathways involving cyclins and cyclin-dependent kinases assumed to be specific to each phase of the cycle. At each of these checkpoints, the cell is checked essentially for its DNA integrity. Genetic defects observed in these molecules (i.e., cyclins, cyclin-dependent kinases) are common features of cancer cells. Nevertheless, each cancer is different concerning its molecular and cellular etiology. These could range from the genetic defects mechanisms and/or the environmental conditions favoring epigenetically harbored homeostasis driving tumorigenesis alongside with the intratumoral heterogeneity with respect to the model that the tumor follows. Conclusions This review is not meant to be an exhaustive interpretation of carcinogenesis but to summarize some basic features of the molecular etiology of cancer and the intratumoral heterogeneity models that eventually bolster anticancer drug resistance for a more efficient design of drug targeting the pitfalls of the models.
... It is widely recognized that accumulation of a significant amount of damaged DNA is a trigger for the halting of cell cycle progression and induction of apoptosis (98). Thus, measures that increase DNA damage and/or decrease the cells' capacity for DNA repair have potential therapeutic benefit. ...
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DNA damage is a double-edged sword for cancer cells. On the one hand, DNA damage–induced genomic instability contributes to cancer development; on the other hand, accumulating damage compromises proliferation and survival of cancer cells. Understanding the key regulators of DNA damage repair machinery would benefit the development of cancer therapies that induce DNA damage and apoptosis. In this study, we found that isoprenylcysteine carboxylmethyltransferase (ICMT), a posttranslational modification enzyme, plays an important role in DNA damage repair. We found that ICMT suppression consistently reduces the activity of MAPK signaling, which compromises the expression of key proteins in the DNA damage repair machinery. The ensuing accumulation of DNA damage leads to cell cycle arrest and apoptosis in multiple breast cancer cells. Interestingly, these observations are more pronounced in cells grown under anchorage-independent conditions or grown in vivo. Consistent with the negative impact on DNA repair, ICMT inhibition transforms the cancer cells into a “BRCA-like” state, hence sensitizing cancer cells to the treatment of PARP inhibitor and other DNA damage–inducing agents.
“Nanodrugs” are entering the clinical practice, where the active compounds or therapeutic agents are incorporated within much larger, nanometer‐scale complexes or particles. For most current nanodrug formulations, the size, size distribution, shape, aspect ratio, stiffness, and the placement of outer ligands that could provide specificity cannot be precisely controlled. These parameters can, however, strongly influence biodistribution, cell uptake, and efficacy. Furthermore, introducing stimuli‐responsive dynamic behavior remains a challenge. Some limitations of other nanomedicines could be overcome with artificial DNA nanostructures (DNs) such as DNA origami (DO) with precisely programmable sizes, shapes, and physical properties. DNs therefore bear great promises in the precise design of nanomedicines. Here, we will introduce the threats to the integrity of DNs, which are noncovalent complexes that are typically only stable in a relatively narrow range of chemical and physical environments. They are, therefore, inherently labile and face a multitude of threats. We will discuss the different chemical, electrostatic, thermal, and enzymatic factors that can degrade DNA. Degradation can affect the hybridization of the two strands of the double‐helix or individual covalent bonds of the backbone or the nucleobases. Finally, we will discuss strategies to stabilize DNA structures for various applications in biomedicine, material science, and biophysics.
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The resilience of ancient DNA (aDNA) in bone gives rise to the preservation of synthetic DNA with bioinorganic materials such as calcium phosphate (CaP). Accelerated aging experiments at elevated temperature and humidity displayed a positive effect of co-precipitated, crystalline dicalcium phosphate on the stability of synthetic DNA in contrast to amorphous CaP. Quantitative PXRD in combination with SEM and EDX measurements revealed distinct CaP phase transformations of calcium phosphate dihydrate (brushite) to anhydrous dicalcium phosphate (monetite) influencing DNA stability.
As a hallmark for cancer treatment, PARP inhibitors can effectively kill tumor cells with a mechanism termed as synthetic lethality, and are used to treat various cancers including ovarian, breast, prostate, pancreatic and others with DNA repair defects. However, along with the clinical trials progressing, the limitations of PARP-1 inhibitors became apparent such as limited activity and indications. Studies have shown that a molecule that is able to simultaneously restrict two or more targets involving in tumors is more effective in preventing and treating cancers due to the enhancing synergies. In order to make up for the shortcomings of PARP inhibitors, reduce the development cost and overcome the pharmacokinetic defects, multiple works were carried out to construct dual targeting PARP inhibitors for cancer therapy. Herein, they were summarized briefly.
Reactive oxygen species formation and resultant oxidative damage to DNA are ubiquitous events in cells, the homeostasis of which can be dysregulated in a range of pathological conditions. Base excision repair is the primary repair mechanism for oxidative genomic DNA damage. One prevalent oxidized base modification, 8-oxoguanine (8-oxoG) is recognised by 8-oxoguanine glycosylase-1 (OGG1) initiating removal and repair via base excision repair (BER). Surprisingly, Ogg1 null mouse embryonic fibroblasts (mOgg1 -/- MEFs) do not accumulate 8-oxoG in the genome to the extent expected. This suggests that there are back-up repair mechanisms capable of repairing 8-oxoG in the absence of OGG1. In the current study we identified components of NER (Ercc1, Ercc4, Ercc5), BER (Lig1, Tdg, Nthl1, Mpg, Mgmt, NEIL3), MMR (Mlh1, Msh2, Msh6) and DSB (Brip1, Rad51d, Prkdc) pathways that are transcriptionally elevated in mOgg1 -/- MEFs. Interestingly, all three nucleotide excision repair genes identified: Ercc1 (2.5 ± 0.2-fold), Ercc4 (1.5 ± 0.1-fold) and Ercc5 (1.7 ± 0.2-fold) have incision activity. There was also a significant functional increase in NER activity (42.0 ± 7.9%) compared to WT MEFs. We also observed up-regulation of both Neil3 mRNA (37.9 ± 1.6-fold) and protein in mOgg1 -/- MEFs. This was associated with a 3.4 ± 0.4-fold increase in NEIL3 substrate sites in genomic DNA of cells treated with BSO, consistent with the ability of NEIL3 to remove 8-oxoG oxidation products from genomic DNA. In conclusion, we suggest that in Ogg1-null cells, upregulation of multiple DNA repair proteins including incision components of the NER pathway and Neil3 are important compensatory responses to prevent accumulation of genomic 8-oxoG.
Ezetimibe represents the first of a new class of agents, the cholesterol absorption inhibitors, able to reduce low-density lipoproteins (LDL)-cholesterol by 15-25% from baseline in monotherapy and on top of statins and fibrates. To-date all the data regarding the efficacy of ezetimibe comes from the studies of its lipid-lowering power. Yet, recent findings from the ENHANCE study on atherosclerosis progression showed that the addition of ezetimibe to simvastatin in patients with heterozygous familial hypercholesterolemia did not affect the mean change in carotid intima-media thickness, although a significant reduction in LDL-cholesterol levels was present. Therefore, we cannot exclude that ezetimibe is treating mainly LDL-cholesterol and not the underlying dyslipidemia. Reviewing all available evidences on the effects on atherogenic small, dense LDL, it seems that ezetimibe produce quantitative rather than qualitative changes in LDL, with small net effects on LDL subclass distribution. Yet, we cannot exclude that clinical and laboratory factors influenced this result. We found important differences in the methodology used to measure LDL size and subfractions and this represents a crucial point, since these methods cannot be fully used interchangeably. In addition, it is reasonable to imagine that ezetimibe may be more effective on small, dense LDL in subjects with hypertriglyceridemia. Further formal cardiovascular event outcome trials are underway and this will provide additional insights into the long-term effects of ezetimibe. Future prospective studies are also needed to clarify to which extent ezetimibe is able to reduce atherogenic dyslipidemia, beyond LDL-cholesterol levels.
Paraoxonase is an enzyme associated with the high-density lipoprotein (HDL) particle. It catalyses the hydrolysis of organophosphates and protects LDL from oxidative modification in vitro by hydrolyzing lipid peroxides, suggestive of a role for paraoxonase in the development of atherosclerosis. Two frequent mutations at the paraoxonase gene locus (PON1) underlie the leucine (Leu allele) → methionine (Met allele) and the glutamine(Gln allele) → arginine(Arg allele) aminoacid substitutions at residues 55 and 192, respectively. These polymorphisms have been associated with increased risk for cardiovascular disease (CVD) in several studies, while others have not found this association. Recently, another member of the PON gene family designated PON2 has been identified. While the PON2 gene product is expressed ubiquitously, its physiological role is unknown. A common polymorphism at codon 311 (Cys→Ser) in the PON2 gene has been described. In our study we assessed the frequency and genotype distribution of the PON1 and PON2 polymorphisms in 197 patients with familial hypercholesterolemia (FH), to determine the possible association between these mutations and susceptibility for CVD. The FH cohort group was divided into subjects with (n=83) and without (n=114) definite clinical manifestations of CVD (FH-Symptomatic and FH-Asymptomatic respectively). The control population consisted of 201 healthy normolipidemic blood donors. All subjects in this study were of Caucasian background. Genotypes were identified by PCR based analysis. With regard to the PON1 polymorphisms 55 and 192, no different distributions of allele frequencies were found between the groups studied. However, we did show an association between the PON2 311 polymorphism and CVD. The frequencies of PON2 Ser311 carriers (Ser/Ser and Cys/Ser) between FH-Symptomatic and both FH-Asymptomatic and controls did show a significant difference (P=0.01 and P=0.02 respectively). In the FH-Symptomatic population, surprisingly, no subjects were homozygous for PON2 Cys311, whereas in the FH-Asymptomatic population nine persons (7.9%) and in the control group 12 persons (6.0%) were homozygous. Our data indicate that the common PON2 polymorphism is associated with clinical manifestations of CVD in FH patients. While PON2 Ser311 carriers seem to be at risk, subjects with the Cys/Cys311 genotype are likely to be protected against the development of premature CVD.
Human serum paraoxonase (PON) is a high density lipoprotein (HDL) associated enzyme capable of hydrolyzing lipid peroxides in vitro. PON has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two frequent mutations at the paraoxonase gene locus (PON1) are the leucine (L allele)-->methionine (M allele) and the glutamine (Q allele)-->arginine (R allele) substitutions at residues 55 and 192, respectively. We have examined the influence of these two polymorphisms on carotid atherosclerosis in familial hypercholesterolemia (FH) patients. The allele frequencies of these two polymorphisms were determined by PCR and restriction fragment analysis, for both the FH population and healthy controls. High resolution B-mode ultrasound was used to assess intima-media wall thickness (IMT) of the carotid artery. No differences were found in allele frequencies between the FH and the control population. In FH patients, the LL, LM and MM genotypes at position 55 occurred in 86 (46.0%), 78 (41.7%) and 23 (12.3%) subjects, respectively, whereas the QQ, QR and RR genotypes at position 192 were found in 90 (48.1%), 79 (42.2%) and 18 (9.6%) individuals. When both polymorphisms were considered separately, no different carotid IMTs were found between the genotype groups. However, our data did show a significant association between the various genotypes of the combined polymorphisms at position 55 and 192 of PON1 and the carotid artery IMT in FH subjects. Subjects with the homozygous wildtype LL/QQ for paraoxonase had the highest mean carotid IMTs when compared to other genotypes, combined. Multiple regression analysis demonstrated age (beta=0.34, P<0.0001), total plasma cholesterol (beta=0.17, P=0. 0109) and the LL/QQ genotype of the PON1 gene (beta=0.22, P=0.0018) to be significant risk factors for carotid atherosclerosis in subjects with FH. The LL/QQ genotype could explain 5.3% of total variance of carotid IMT. In conclusion, this is the first study to report an independent association between the combined PON1 polymorphism genotypes and carotid wall thickness. The homozygous wildtype LL/QQ for PON1 may represent an additional risk factor for carotid atherosclerosis in subjects with FH.
Despite contemporary therapies for acute coronary syndrome (ACS), morbidity and mortality remain high. Low levels of high-density lipoprotein (HDL) cholesterol are common among patients with ACS and may contribute to ongoing risk. Strategies that raise levels of HDL cholesterol, such as inhibition of cholesterol ester transfer protein (CETP), might reduce risk after ACS. Dal-OUTCOMES is a multicenter, randomized, double-blind, placebo-controlled trial designed to test the hypothesis that CETP inhibition with dalcetrapib reduces cardiovascular morbidity and mortality in patients with recent ACS. The study will randomize approximately 15,600 patients to receive daily doses of dalcetrapib 600 mg or matching placebo, beginning 4 to 12 weeks after an index ACS event. There are no prespecified boundaries for HDL cholesterol levels at entry. Other elements of care, including management of low-density lipoprotein cholesterol, are to follow best evidence-based practice. The primary efficacy measure is time to first occurrence of coronary heart disease death, nonfatal acute myocardial infarction, unstable angina requiring hospital admission, resuscitated cardiac arrest, or atherothrombotic stroke. The trial will continue until 1,600 primary end point events have occurred, all evaluable subjects have been followed for at least 2 years, and 80% of evaluable subjects have been followed for at least 2.5 years. Dal-OUTCOMES will determine whether CETP inhibition with dalcetrapib, added to current evidence-based care, reduces cardiovascular morbidity and mortality after ACS.
High blood pressure is a very common disease in hypercholesterolemic and diabetic patients and contributes to the increase in cardiovascular risk. Inhibitors of 3OH-3methyl-glutaryl-coenzyme A reductase are the most effective and widely used cholesterol-lowering drugs. They significantly reduce the risk of cardiovascular events and death in both primary and secondary prevention of cardiovascular disease. Although the long-term benefit by statin treatment is largely attributed to their cholesterol-lowering action, increasing attention focuses on additional actions called "pleitropic effects" that might explain the cardiovascular protection seen shortly after the initiation of therapy. Very few and small studies have investigated the antihypertensive effect of statins in patients with hypertension associated with hypercholesterolemia, and the results of recently published large statin studies (albeit not designed to answer this question) have attracted the interest on this subject. Many other studies, also not specifically aimed at the evaluation of the statins' antihypertensive effect, have provided information concerning changes in blood pressure during treatment with statins, but severe limitations such as inadequate study design, small or very small sample size, too short of a treatment period, and modification of concomitant antihypertensive therapy have prevented finding a definitive effect on blood pressure. From the available results, it appears consistent that statins may be useful in hypertensives with high serum total cholesterol, in those whose hypertension is not well controlled with antihypertensive agents even without high serum total cholesterol, in hypertensive subjects well controlled with antihypertensives without high serum cholesterol when they have high polymerase chain reaction levels, in those who require preventive measures because of other concomitant cardiovascular risk factors, or when they require secondary prevention. Future research could further characterize the impact of statin use alone or in combination with antihypertensive agents to delay the development of Stage 1 hypertension in prehypertension.