Carcinogenesis vol.27 no.5 pp.883–892, 2006
doi:10.1093/carcin/bgi319
Advance Access publication February 20, 2006
REVIEW
DNA damage responses and their many interactions with the replication fork
Paul R.Andreassen1,2, , Gary P.H.Ho3 and Alan
D.D’Andrea3
1
Division of Experimental Hematology, Cincinnati Children’s Hospital
Medical Center and 2Department of Pediatrics, University of Cincinnati
College of Medicine, Cincinnati, OH 45229, USA and 3Department of
Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School,
Boston, MA 02115, USA
To whom correspondence should be addressed at: Cincinnati Children’s
Hospital Medical Center, 3333 Burnet Avenue ML 7013, Cincinnati,
OH 45229, USA. Tel: +1 513 636 0499;
Email: [email protected]
The cellular response to DNA damage is composed of cell
cycle checkpoint and DNA repair mechanisms that serve to
ensure proper replication of the genome prior to cell division. The function of the DNA damage response during
DNA replication in S-phase is critical to this process.
Recent evidence has suggested a number of interrelationships of DNA replication and cellular DNA damage
responses. These include S-phase checkpoints which suppress replication initiation or elongation in response to
DNA damage. Also, many components of the DNA damage
response are required either for the stabilization of, or for
restarting, stalled replication forks. Further, translesion
synthesis permits DNA replication to proceed in the
presence of DNA damage and can be coordinated with
subsequent repair by homologous recombination (HR).
Finally, cohesion of sister chromatids is established
coincident with DNA replication and is required for
subsequent DNA repair by homologous recombination.
Here we review these processes, all of which occur at, or
are related to, the advancing replication fork. We speculate that these multiple interdependencies of DNA replication and DNA damage responses integrate the many steps
necessary to ensure accurate duplication of the genome.
Introduction
Fidelity in cell division is requisite for normal development
and for the suppression of tumorigenesis (1). One such process
in cell division which must be completed with fidelity is DNA
replication during S-phase. Cell cycle checkpoints, which
delay cell cycle progression until critical steps are completed
accurately, cooperate with DNA repair processes to ensure
the accurate replication of the genome (1–3). Various
mechanisms of DNA repair serve to ensure fidelity in replication by repairing spontaneous or environmentally-induced
errors, either before or after the replication of a particular
DNA template (4,5).
Abbreviations: ATM, ataxia telangiectasia mutated; ATR, ATM and
Rad3-related; BLM, Bloom syndrome; BRCA1 and 2, BReast CAncer genes/
proteins 1 and 2; DSBs, double-strand DNA breaks; FANCD1 and FANCD2,
Fanconi anemia proteins D1 and D2; HR, homologous recombination; IR,
ionizing radiation; NBS, Nijmegen breakage syndrome; SMC, structural maintenance of chromosomes; TLS, translesion synthesis; UVC, ultraviolet irradiation.
#
Many observations have suggested a relationship between
normal DNA replication and cellular DNA damage responses.
DNA damage, such as that induced by UV radiation or bifunctional crosslinking agents, can induce S-phase arrest (6–8). In
such cases, DNA repair is required for the continuation and
completion of DNA replication. The interrelationship of DNA
replication and DNA repair is also apparent from the involvement of proteins, such as proliferating cell nuclear antigen
(PCNA) and replication protein A (RPA), in both processes
(9–11). PCNA is an accessory factor for DNA polymerase
d (12,13) and RPA is required for the initiation of DNA
replication (14).
A further example of the interconnection of S-phase DNA
replication and DNA damage responses is evident in the finding that the ataxia telangiectasia mutated (ATM) and ATM and
Rad3-related (ATR) checkpoint kinases, which mediate the
responses to double-strand DNA breaks (DSBs) and stalled
replication forks, respectively, are involved in regulating the
timing of the initiation of replication either in the presence or
absence of exogenous DNA damage (15,16). Also, in response
to DNA damage, ATM and ATR phosphorylate the minichromosome maintenance (MCM) proteins, which are involved in
the initiation of DNA replication (17,18).
Whereas both non-homologous end joining (NHEJ) and
homologous recombination (HR) have a role in the repair of
DSBs, HR is specifically activated in S-phase, unlike NHEJ
(19,20). The recognition of certain types of damage, such as
DNA interstrand crosslinks, occurs during S-phase (21).
Such observations provide further evidence for the interconnections of DNA replication and cellular responses to DNA
damage.
Recent work has yielded mechanistic insight into numerous
interactions at the replication fork between S-phase DNA replication and DNA damage responses. Here we will review four
such interactions (shown schematically in Figure 1). First, the
checkpoint kinases, ATM and ATR, mediate an intra-S checkpoint which suppresses DNA replication in response to different types of DNA damage (22–24). This involves both blocks
to replication initiation and the phosphorylation of a multitude
of proteins involved in DNA repair (2,25). Second, ATR and
the Chk1 kinase, which is activated by ATR (26,27), are
required for the response to stalled DNA replication (28–
30). This response involves both mechanisms to stabilize
the stalled replication fork and mechanisms, including HR,
required to restart the stalled replication fork (31–33). Recent
results have implicated a number of different DNA repair
proteins in this process. Third, recent work has elucidated
the role of polymerase switching in translesion synthesis
(TLS), which allows continuation of DNA replication by
bypassing the lesion (34,35). HR can then cooperate with
TLS to mediate the repair of a lesion that stalls the replication
fork (34). And fourth, DNA replication generates sister chromatids linked by cohesin proteins. This cohesion is required
for subsequent DNA repair by HR (36).
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P.R.Andreassen, G.Ho and A.D.D’Andrea
Fig. 1. Overview of important interactions between the DNA replication and DNA damage response processes. When the replication fork encounters a DNA
lesion, many components of the cellular response to DNA damage are activated. (A) Checkpoints mediate the suppression of DNA replication when DNA
damage is encountered. A key element of this is a block to the initiation of replication origins which would normally be fired subsequently. (B) When a
lesion is encountered, checkpoints also stabilize stalled replication forks against collapse by maintaining their association with replicative polymerases.
Subsequently, the cell restarts stalled replication forks using HR. (C) Another response to stalled replication is replication bypass of certain lesions. Lesion
bypass is mediated by TLS polymerases and can be coupled with subsequent repair by HR. (D) Cohesion of sister chromatids, which is established during
DNA replication, is required for efficient repair of DSBs by HR. It is important to note that each of the DNA damage response processes described above
occur in proximity to, or are related to, the replication fork.
Here, we detail recent insights into how the processes of
DNA replication and DNA damage responses cooperate to
ensure fidelity in cell division. We suggest that these interrelationships, which occur at the replication fork, serve to coordinate the many processes involved in repairing DNA damage
generated both spontaneously and by exogenous sources.
The vital importance of this cooperation is illustrated by the
many chromosome instability and cancer predisposing diseases, including Bloom syndrome (BLM), ataxia telangiectasia
884
(AT), Nijmegen breakage syndrome (NBS) and Fanconi
anemia (FA), which represent defects in the cellular response
to DNA damage and which thereby result in inaccurate replication of the genome (5,37).
The S-phase checkpoint suppresses DNA replication in
response to DNA damage
There are various S-phase checkpoints, including checkpoints
which suppress entry into mitosis until DNA replication has
DNA damage response during replication
been completed (S–M checkpoint) (38) and checkpoints which
block DNA replication in S-phase cells in the presence of
DNA damage (intra-S-phase checkpoint) (2). Recent progress
in understanding the function of the intra-S-phase checkpoint
illustrates ways in which DNA synthesis and the DNA damage
response interact and will be considered here.
Following the exposure of cells to either ionizing radiation
(IR) or ultraviolet irradiation (UVC), both the initiation of
DNA replication and the elongation of nascent DNA strands
are inhibited (39,40). But quantitatively, inhibition of the initiation of DNA replication is the major component of the intraS-phase checkpoint (22,39). Inhibition of replication initiation
in response to fork progression stalled or blocked by DNA
damage, such as UVC, is dependent upon the ATR/MEC1
checkpoint kinase in yeast (41), in Xenopus extracts (15)
and in mammalian cells (22). By contrast, inhibition of the
initiation of DNA replication following DSBs is independent
of the replication fork (2).
Critical steps which regulate the initiation of DNA replication have been elucidated recently. The steps involved in the
assembly of the pre-replication complex and in the activation
of origin unwinding have been reviewed elsewhere (42). In
brief, a pre-replicative complex containing the origin recognition complex (ORC), Cdc6, Cdt1 and six MCM proteins
(MCM2–7), is assembled prior to the initiation of replication.
Cdc7 and Cdk2 (cyclin dependent kinase 2) act in a sequential
manner to load Cdc45 at the origin (43). Binding of Cdc45 and
then RPA results in origin unwinding and binding of the primase DNA polymerase a, which begins replication (44).
A defect in the ability to suppress DNA synthesis following
exposure to IR, termed radio-resistant DNA synthesis (RDS),
was first described for cells derived from AT patients (39)
deficient for the ATM checkpoint kinase (45). Recent work
has brought mechanistic insight into how ATM inhibits DNA
synthesis following exposure to IR. ATM coordinates two
parallel branches of response to IR (25). The first branch directly inhibits the initiation of replication at origins to be fired
subsequently. ATM phosphorylates and activates both the
Chk1 and Chk2 protein kinases, which in turn phosphorylate
the Cdc25A phosphatase at multiple sites (24,46). This leads to
Cdc25A degradation (24,47). As a result, the inhibitory phosphorylation of the Cdk2 kinase is maintained (24) and this
suppresses the loading of Cdc45 at the origin of replication
(25). While it has been reported that AT cells, deficient for
ATM, have a partial defect in inhibiting the initiation of DNA
synthesis following exposure to UVC (48), ATR and Chk1
have a predominant role in this process (22,49). Nevertheless,
similar to IR, exposure to UVC leads to the degradation of
Cdc25A and the inhibition of Cdk2 kinase activity (47).
The second branch of IR-induced suppression of DNA synthesis involves ATM-dependent phosphorylation of a number
of proteins involved in the DNA damage response, which act to
maintain chromosome stability. These include NBS1 (Nijmegen breakage syndrome protein 1), BRCA1 (BReast CAncer
protein 1), BRCA2/FANCD1 (BReast CAncer protein 2=
Fanconi anemia protein D1) and FANCD2 (Fanconi anemia
protein D2). Abrogation of these phosphorylation events
results in RDS (50–54). Further, ATM-dependent or ATRdependent phosphorylation of the cohesin protein, SMC1
(structural maintenance of chromosomes 1), a member of a
family of proteins involved in sister chromatid cohesion, is also
required to suppress DNA synthesis following exposure to IR
(55,56) or UVC (57), respectively. Recently, it has been
demonstrated that ATM-dependent phosphorylation of
NBS1 and BRCA1 is required for the localization of activated
ATM to sites of DSBs (58). The phosphorylation of NBS1
and BRCA1 are interdependent and result in the downstream
phosphorylation of SMC1 (58). While it is unknown how
phosphorylated SMC1 affects the intra-S-phase IR checkpoint,
it has been determined that it is not through inhibition of
Cdc45 loading at the origin (25).
It has recently been reported that deletion of the fission
yeast homolog of NBS1 results in RDS (59). Interestingly,
these authors propose a model in which NBS1 does not
directly inhibit DNA synthesis following DNA damage but
instead mediates recombination-dependent repair that slows
DNA synthesis. This appears to be consistent with the finding
that NBS1 does not regulate Cdc45 loading, and by extension
origin firing, following DNA damage in mammalian cells (25).
It is important to note that ATM, NBS1 and BRCA1 have all
been implicated in HR in vertebrate cells (60–62) and that
recent experimental evidence suggests the slowing of the replication fork by HR in mammalian cells (63). While evidence exists for interactions of NBS1 (64) and BRCA1 (65)
with FANCD2, the functional relationship of FANCD2, or of
BRCA2/FANCD1, to the ATM–NBS1–BRCA1–SMC1
branch of this S-phase checkpoint has not been determined.
A model for the cooperation of the two branches of the intra-Sphase checkpoint affected by ATM in response to IR is shown
in Figure 2.
Repair-dependent slowing of the replication fork appears to
be consistent with old reports suggesting that in mammalian
cells either IR or UVC slow elongation of nascent DNA strands
at sites where DNA synthesis had already been initiated
(39,40). Importantly, cells from Xeroderma Pigmentosum
(XPV) patients, which are deficient for the repair of DNA
damage induced by UVC, display an excessive slowing of
elongation following exposure to UVC (40). In this case,
defective DNA repair results in increased DNA damage and
this further slows the replication fork.
Role of the DNA damage response in restarting/stabilizing
stalled replication forks
The DNA replication and DNA damage response processes
also cooperate in protecting the cell against stalled replication
(recently reviewed (31,32)). This was first characterized
extensively in bacteria, but more recently similar mechanisms
have been found to function in yeast and vertebrate cells.
Replication can stall due to double-strand or single-strand
DNA breaks that arise during DNA synthesis, due to adducts
resulting from reactive oxygen species (ROS) in the cell, or
due to adverse secondary structures present in DNA
(31,66,67). Failure to stabilize stalled replication forks can
result in their collapse and ultimately in genetic instability
(66–70).
Mechanisms which stabilize stalled replication forks result
in the continued association of DNA polymerase complexes
with nascent DNA strands (71). This is important, since it
permits efficient resumption of DNA synthesis once it has
restarted. Recovery of stalled replication forks involves HR
and will be discussed below. Two elements of the DNA damage response: checkpoint kinases, including Chk1 and MEC1/
ATR, and RecQ family helicases are central to both stabilization and recovery of stalled replication forks. These components have functions which are conserved from yeast to
mammals. The roles of checkpoint kinases (72) and RecQ
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P.R.Andreassen, G.Ho and A.D.D’Andrea
Fig. 2. The ATM checkpoint kinase coordinates a two-branched response to IR that suppresses DNA replication. In one branch (left), phosphorylation of
Chk2 (and Chk1) kinase activates the phosphorylation of the Cdc25A phosphatase thereby targeting it for degradation. This maintains inhibitory
phosphorylation of the Cdk2 kinase and prevents the loading of Cdc45, resulting in the suppression of the initiation of DNA synthesis. The second branch
(right) does not inhibit the loading of Cdc45, but does lead to the recruitment of SMC1 in a phospho-NBS1- and phospho-BRCA1-dependent manner.
We propose that HR-dependent repair, mediated by a protein complex including SMC1, NBS1 and BRCA1, blocks the advance of the replication fork.
helicases (4) in the cellular response to stalled replication have
been reviewed recently.
While both checkpoints (41,68,71,73) and RecQ helicases
(71,74) have a role in preventing the collapse of stalled replication forks, other proteins have also been identified which
play a role in this process. This includes BRCA2 (75), which
has an important role in HR (76). It is interesting that, by its
role in HR, BRCA2 may also have an important role in
restarting stalled replication forks.
Potential roles and mechanisms for HR in restarting stalled
replication have been recently reviewed by Helleday (33).
Increasingly, components involved in the processing of stalled
replication forks are being identified and their relationship to
HR determined. Fission yeast and budding yeast RecQ
helicases, Rqh1 and Sgs1, respectively (74,77) and BLM
(78), a mammalian RecQ homolog, are required to restart
stalled replication forks. Importantly, these RecQ helicases
regulate the formation of Holliday junction recombination
intermediates (79,80). RecQ helicase-dependent regression
of stalled replication forks can lead to the formation of Holliday junctions, which have been visualized in yeast (81). The
Mus1-Eme1 endonuclease resolves Holliday junctions in vitro
(82) and is required for the processing of stalled replication
forks (83). It has been proposed that an increased frequency
or complexity of lesions at stalled replication forks leads
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to HR involving RAD51-dependent strand invasion (84).
The RecQ helicases may suppress RAD51-dependent strand
invasion and favor restarting the stalled replication fork by
fork regression and subsequent resolution by the Mus1Eme1 resolvase (84). Accordingly, a deficiency for Rqh1, Sgs1
or BLM results in an increased frequency of HR (77,84,85).
Further evidence for a role of HR in restarting stalled replication forks comes from the finding that Rad51 foci and HR
are stimulated by stalled replication (86–88). Additionally,
Poly(ADP-ribose) polymerase-1 (PARP-1) is required in an
unknown manner to restart stalled replication (89).
Recent work has provided insight into steps involved in the
recruitment of machinery involved in the stabilization and/or
reactivation of stalled replication forks in mammalian cells.
The single-strand DNA binding complex, RPA, is required for
the recruitment of ATR at sites of stalled replication (90) and
appears to regulate the Rad51 recombinase (91–93). Importantly, BLM is recruited to the stalled replication fork in
mammalian cells in a process that requires the checkpoint
mediator 53BP1 (28). The recruitment of both 53BP1 and
BLM is regulated by the Chk1 kinase, which is activated
by ATR (26,27). It has also been reported that ATR
phosphorylates BLM directly (78). Additionally, BLM is
required for the recruitment of p53, which then presumably
regulates RAD51 and HR (84). Another element, BRCA1, is
DNA damage response during replication
phosphorylated by and colocalizes with, ATR in response to
stalled replication (30). The relationship of BRCA1 and BLM
recruitment is unknown. While the formation and colocalization of phosphorylated histone H2AX, 53BP1 and BRCA1 foci
occurs in response to stalled replication (94), recruitment of
53BP1 and BLM to stalled replication forks does not require
H2AX (28). A model for the recruitment of DNA damage
response proteins to the stalled replication fork is shown in
Figure 3.
TLS (bypass) allows S-phase DNA replication to proceed
prior to repair of the lesion by HR
Another response to DNA damage that stalls DNA replication
is replication bypass, also known as TLS. The process of TLS
is an interesting example of the interactions of replicative
DNA synthesis and DNA damage responses. TLS utilizes
lower fidelity Y family DNA polymerases, including pol eta
(h), iota (i), kappa (k), REV1 and the B family polymerases
REV3/7 (z) (recently reviewed in refs 35 and 95). These polymerases function specifically in the replication of damaged,
but not undamaged, DNA. This allows replication of lesions
that would otherwise block DNA replication.
DNA repair processes, such as base excision repair (BER)
and nucleotide excision repair (NER), remove most of the
DNA damage present in the cell. But damage which escapes
repair by these processes can stall replication, lead to fork
collapse, and ultimately result in genetic instability (34,91).
Work more than three decades ago demonstrated that mammalian cells are capable of synthesizing intact daughter strands
of DNA in the presence of persistent DNA damage on the
parental strand (96). Recent work has led to the identification
and characterization of translesion polymerases involved in
this process (35,95).
While the relative importance of TLS and HR in responding to replication blocking lesions in mammalian cells is
unknown, both processes cooperate to prevent replication
fork collapse in the chicken B-cell line, DT40 (97,98). Interestingly, recent work with DT40 cells has indicated a potential
role for TLS in HR itself (98–100). Importantly, unhooked
repair intermediates for DNA interstrand crosslinks induce
replication stalling and DSBs. Gap filling by TLS stabilizes
the lesion prior to subsequent repair by mechanisms such as
NER and HR (99).
Homologs involved in TLS, as well as HR, are conserved
from bacteria to humans (34,101). Because of the lower fidelity
of Y family polymerases (35,95), it is critically important that
their use is restricted to replicating lesions that have not been
repaired by other means and which will thereby stall DNA
replication. This is accomplished by polymerase switching.
Important steps in polymerase switching have recently been
elucidated (101). The target of regulation is PCNA, the processivity factor for DNA polymerase d in leading strand DNA
synthesis (12,102). Monoubiquitination of PCNA in yeast and
humans requires the RAD6/RAD18 ubiquitination machinery
(103,104) and is essential for TLS (104,105). PCNA associates
both with pol d and with the Y family polymerases h, i and k
(104,106–108). A switch to a Y family polymerase, when pol d
(or pol e) encounters a blocking lesion, allows DNA replication
across the lesion. Because Y family polymerases copy undamaged DNA with lower processivity than damaged DNA, this
allows a switch back to pol d or e following lesion bypass
(109). Coupled with the 30 -50 exonuclease activity of pol d
and e, this can result in error-free bypass depending on the
Fig. 3. Model for the recruitment of proteins involved in stabilizing or
restarting the stalled replication fork. The single-strand DNA binding
complex, RPA, is recruited to exposed single-strand DNA. This leads to the
recruitment of the Rad51 recombinase and to the recruitment and activation
of ATR. ATR then phosphorylates BRCA1, enabling BRCA1 recruitment
and also phosphorylates the BLM helicase. Importantly, ATR
phosphorylates and activates Chk1. Chk1 is required for the
53BP1-dependent recruitment of BLM. Once in place BLM recruits p53,
which may regulate Rad51-dependent HR involved in restarting the
stalled replication fork. BLM is required to stabilize and restart stalled
replication forks.
Fig. 4. Monoubiquitination of PCNA mediates polymerase switching when
the replication fork encounters DNA damage. Normal replicative DNA
synthesis is carried out by DNA pol d, in association with the processivity
factor, PCNA. When DNA damage is encountered, PCNA is
monoubiquitinated by Rad6/Rad18. This allows a switch to TLS
polymerases, such as pol h and pol k, which then, in association with
PCNA, synthesize across the lesion.
DNA lesion (95,110,111). Whether monoubiquitination favors
the dissociation of pol d with the primer terminus, favors
association of TLS polymerases with the primer terminus,
or both, is unknown (101). It is clear though, that the association of PCNA with sites of DNA damage is regulated through
its monoubiquitination (112). The interaction between processive DNA replication and the DNA damage response in
polymerase switching is summarized in Figure 4.
A variant of XPV, which is associated with sunlight-induced
cancers and a defect in the replication of DNA containing UV
dimers, represents a mutation in the translesion polymerase h
(113). UV dimers represent one type of replication blocking
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P.R.Andreassen, G.Ho and A.D.D’Andrea
Fig. 5. HR-dependent repair of DSBs is mediated by cohesion established during DNA replication. We propose that a tetrameric cohesin complex that is
associated with the pre-replication complex (pre-RC) via Scc2 establishes cohesion between sister chromatids as the replication machinery advances the
replication fork. The cohesin complex then cooperates with RAD50, which is in a complex with MRE11 and NBS1, to mediate HR-dependent repair of
DSBs using the paired sister chromatid.
lesion which can be bypassed by translesion polymerases. The
cancer predisposition associated with mutation of polymerase
h illustrates the critical importance of the function of translesion polymerases in response to DNA damage encountered by
the replication fork.
Role of cohesion in DNA repair
Cohesion of sister chromatids is mediated by a family of
proteins called cohesins (114,115). The establishment of cohesion is coupled to the DNA replication machinery (reviewed
in (114,116)) and cohesion is integral to the DNA damage
response. As discussed above, ATM-dependent phosphorylation of the cohesin protein SMC1 is required for the intra-S
checkpoint following exposure to IR (55,56,58). In addition,
it is becoming apparent that cohesins have an important role
in HR.
In a mitotic cell cycle, cohesin is composed of a tetrameric
complex of Scc1, Scc3 and two SMC (structural maintenance
of chromosomes) members, SMC1 and SMC3 (117–119).
Loading of cohesins onto chromatin is dependent on a noncore subunit, Scc2, both in yeast and in frog extracts (117,120–
122). While the specific timing of cohesin loading differs
between yeast and either Xenopus extracts or mammalian
cells, recent work suggests that Scc2 recruits cohesin to the
pre-replication complex which regulates the initiation of replication (121–123). At least in Xenopus extracts, however,
cohesin loading does not require initiation of DNA replication.
Once loaded cohesins are in place, cohesion is established as
the nascent sister chromatid is generated during DNA
replication. There are a number of interactions between the
replication machinery and elements involved in establishing
cohesion (recently reviewed in refs 114 and 116). Among
these, Ctf7/Eco1, a non-cohesin subunit required to establish
cohesion, interacts genetically with PCNA (117,124). And the
replicative polymerase, pole, associates with SMC1 and Ctf7/
Eco1 (125). Presumably this interaction between polymerases
and cohesin components is established after the initiation of
replication. Alternative replication factor C (RFC) complexes
which are required for sister chromatid cohesion have been
reported (126,127). Ctf7/Eco1 binds to RFC and alternative
RFC complexes (128). In this way, RFC complexes, which
load either PCNA or the Rad9-Rad1-Hus1 checkpoint complex
onto chromatin, potentially link cohesion to DNA replication
and checkpoint signaling (116,128). Importantly, a human
homolog of yeast EcoI, Esco2, is mutated in Roberts syndrome
(129). Mutation of EcoI in yeast (130) or Esco2 (131) in
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humans is associated with sensitivity to DNA damaging
agents, demonstrating another linkage between the establishment of cohesion in S-phase and subsequent function of DNA
damage responses. In this context, it is interesting that a yeast
screen for non-cohesin components involved in cohesion identified genes involved in the DNA damage response. This
includes Sgs1, which is involved in the response to stalled
replication as discussed earlier and genes involved in DNA
repair (132).
The finding that cohesin can relocalize to sites of DNA
damage suggests a more direct role for cohesins in the
DNA damage response (133). Indeed, cohesins play a specific
role in the repair of DSBs by HR. Cohesion of sister chromatids, which are the preferred template for HR, is required for
efficient repair of DSBs by HR (36). Further, Rad21, which is
required for the repair of DSBs induced by IR in fission yeast,
is the cohesin Scc1 (36,134,135). Interestingly, in yeast,
RAD50, which is part of the MRE11–RAD50–NBS1 complex,
appears to function in a pathway with rad21/Scc1 to promote
the utilization of the sister chromatid to repair DSBs by HR
(136). Additionally, in mammalian cells SMC1 is a component
of the RC-1 recombination complex (137). It has recently been
reported that cohesin can also be recruited to sites of DSBs in
budding yeast during G2, independent of the replication fork
(138). Thus, cohesion established during DNA replication may
have a specific function in DNA repair during S-phase. The
coordination of replication-coupled cohesion with DSB repair
is summarized in Figure 5.
It has recently been determined that degradation of the
cohesin Scc1 is required both for anaphase separation of chromosomes and for interphase DNA repair (139). Thus, the
release of sister chromatid cohesion may also be an important
step in repair.
Conclusions
Cellular DNA damage responses, which are composed of cell
cycle checkpoints and DNA repair mechanisms, and S-phase
DNA replication are highly interrelated and interdependent.
Recent work has added to our understanding of the mechanistic
basis of these interrelationships. Strikingly, S-phase DNA
replication and DNA damage responses are related in a
number of processes, including S-phase checkpoints, the cellular response to stalled replication forks, translesion synthesis
to bypass unrepaired DNA lesions, and sister chromatid
cohesion. We suggest that this allows the coordination of
DNA damage response during replication
the many steps involved in faithfully replicating DNA. For
example, the checkpoint mechanisms which sense and signal
the cellular response to DNA damage are also centrally important for stabilizing and processing the stalled replication fork.
Thus, the cell utilizes the same signaling mechanisms to
attempt to prevent stalling of replication forks, to avoid
their collapse, and ultimately, if necessary, to restart the stalled
replication fork. Another example of the coordination of the
steps required for faithful replication of DNA is the potential
for the combined action of HR and lesion bypass by TLS. In
this way, the cell is capable of responding to a broader range of
lesions which can stall replication.
It is important to point out that the various processes
involved in assuring accurate DNA replication may be occurring simultaneously. For example, cohesion is established as
sister chromatids are generated by DNA synthesis. A template
for DNA repair by HR is therefore potentially generated as
lesions arise during DNA synthesis. As another example,
reversion of stalled replication forks can allow the generation
of a Holliday junction required to restart stalled replication.
Given the potentially close temporal proximity of events
required for faithful DNA replication during S-phase, it may
not be surprising that these processes are integrated together.
We suggest that it is this integration, which is achieved by
coordination of S-phase DNA synthesis and the DNA damage
response, which allows the replication of the genome with the
highest possible fidelity.
Conflict of Interest Statement: None declared.
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Received July 28, 2005; revised September 5, 2005;
accepted December 17, 2005