Mutagenesis

Mutagenesis Advance Access originally published online on November 28, 2005
Mutagenesis 2006 21(1):3-9; doi:10.1093/mutage/gei063

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REVIEW

DNA damage checkpoints in mammals

Hiroyuki Niida and Makoto Nakanishi^*

Department of Biochemistry and Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan

	Abstract

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DNA damage is a common event and probably leads to mutation or deletion within chromosomal DNA, which may cause cancer or premature aging. DNA damage induces several cellular responses including DNA repair, checkpoint activity and the triggering of apoptotic pathways. DNA damage checkpoints are associated with biochemical pathways that end delay or arrest of cell-cycle progression. These checkpoints engage damage sensor proteins, such as the Rad9-Rad1-Hus1 (9-1-1) complex, and the Rad17–RFC complex, in the detection of DNA damage and transduction of signals to ATM, ATR, Chk1 and Chk2 kinases. Chk1 and Chk2 kinases regulate Cdc25, Wee1 and p53 that ultimately inactivate cyclin-dependent kinases (Cdks) which inhibit cell-cycle progression. In this review, we discuss the molecular mechanisms by which DNA damage is recognized by sensor proteins and signals are transmitted to Cdks. We classify the genes involved in checkpoint signaling into four categories, namely sensors, mediators, transducers and effectors, although their proteins have the broad activity, and thus this classification is for convenience and is not definitive.

	Sensors of DNA damage

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The first step in the initiation of activity of DNA damage checkpoints is recognition of the DNA damage (Figure 1). Studies in yeasts and mammals have demonstrated that Rad9, Rad1, Hus1 (1) and Rad17 are essential factors that activate checkpoint signalings (2–4) (see Table I). In both human and yeast systems, Rad9, Rad1 and Hus1 form a heterotrimeric complex (the 9-1-1 complex), whose structure resembles a proliferating cell nucleus antigen (PCNA)-like sliding clamp (5). However, Rad17 interacts with four small replication factor c (RFC) subunits, Rfc2, Rfc3, Rfc4 and Rfc5, to form an RFC-related complex, which acts as a clamp-loading complex and is related to the PCNA clamp loader (6–9). Once DNA is damaged, the 9-1-1 complex is recruited to the damage site under the regulation of Rad17 complex (10,11). The chromatin-bound 9-1-1 complex then facilitates phosphorylation mediated by ataxia telangiectasia and Rad-3-related (ATR) and ataxia telangiectasia mutated (ATM). In yeast, the recruitment of Mec1-Ddc2 [a yeast homolog of ATR–ATR-interacting protein (ATRIP)] to sites of DNA damage is independent of the Rad17 and 9-1-1 complexes (10,11). Recent evidence supports a model in which Ddc2 binds to RPA-coated single-stranded DNA (ssDNA), subsequently recruiting Mec1-Ddc2 (ATR–ATRIP) at sites of DNA damage(12).

View larger version (13K): [in this window] [in a new window]   Fig. 1.. Conceptual organization of the signal transduction of checkpoint responses. DNA damages are recognized by sensor proteins. The signals are transmitted to tranducers (mainly kinases) and the regulated transducer molecules suppress effector kinases, such as Cdks and Cdc7, thereby arresting the cell cycle at the specific phases.

 

View this table: [in this window] [in a new window]   Table I.. Classification of genes involved in DNA damage checkpoints

 

	Mediator molecules

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BRCT proteins
In mammals, there are four mediator-type proteins that contain BRCA1 C-terminus repeat (BRCT) domains that serve protein–phosphoprotein interaction modules (13,14). The p53 binding protein 1 (53BP1) is thought to be a homolog of fission yeast Crb2 and budding yeast Rad9 (15–19). Mediator of DNA damage checkpoint 1 (MDC1) functions as a molecular bridge between histone H2A isoform (H2AX) and Nijmegen breakage syndrome1 (NBS1) in the MRE11–Rad50–NBS1 (MRN) complex (20–22). Topisomerase binding protein 1 (TopBP1) is probably a homolog of fission yeast Cut5 (23,24), and breast cancer susceptibility gene 1, BRCA1, is a causative gene of familial breast cancer (25). Unlike sensor proteins that accumulate at the sites of DNA damage in an ATM-independent manner, recruitment of these mediator proteins that form microscopically visible ‘foci’ depends on the phosphorylation of H2AX by ATM (26–29), a modification that marks chromatin regions spanning megadaltons of DNA flanking each double-strand break (DSB) (30). Although BRCT domain mediator proteins are unlikely to initially target the activated ATM to sites of DNA damage, a process that is dependent on the functional MRN complex (31–36), the sustained multiprotein interactions controlled by these mediators appear to facilitate ATM signaling. In addition to these bona fide mediators, other proteins such as H2AX (37) and structural maintenance of chromatin 1 (SMC1) (31) also play essential roles in the activation of checkpoint kinases.

	Transducers

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ATM and ATR
In mammals, signals initiated by the sensors very rapidly transduce to ATM and ATR kinases, which are both extremely large proteins that phosphorylate a great number of substrates. ATM is a 350 kDa oligomeric protein containing many HEAT huntingtin, elongation factor 3, a subunit of protein phosphatase 2A and TOR1 (HEAT) motifs (38,39). It exhibits significant homology to phosphoinositide 3-kinases (PIKK), but lacks lipid kinase activity (40,41). In humans, mutations in ATM cause ataxia telangiectesia, a rare autosomal recessive disease characterized by cerebellar degeneration, immunodeficiency, genome instability, clinical radiosensitivity and predisposition to cancer (40). Cells lacking ATM are viable and patients and mice survive, suggesting that ATM is not essential for a normal cell cycle or differentiation (42). The protein kinase activity of ATM is minimal or low but can be stimulated in vivo by agents that induce DSBs in vivo and by linear DNA in vitro. Activated ATM phosphorylates many proteins, including breast cancer 1 (BRCA1) (43), NBS1 (44), Chk2 and p53 (45,46), as well as itself (39) in the sequence context of SQ or TQ (Figure 2). Recently, the identification of a damage-induced phosphorylation site (Ser1981) revealed a new mechanism for ATM regulation by which a rapid and sensitive switch for checkpoint signals is permitted (39). ATM under unstressed conditions exists as a homodimer in which the kinase domain is physically blocked by tight intermolecular binding to a protein domain at around Ser1981. DSBs cause a conformational change in the ATM protein that stimulates the kinase to phosphorylate Ser1981 by intermolecular autophosphorylation, resulting in dissociation of the homodimer. The conformational change does not appear to require binding to the site of DNA damage, but results from some change in the higher-order chromatin structure. Such chromatin changes can be sensed at some distance away from the DSB site. However, detailed information on the nature of these chromatin changes and the manner in which ATM recognizes this change remains elusive.

View larger version (32K): [in this window] [in a new window]   Fig. 2.. Schematic molecular organization of the DNA damage checkpoints throughout the cell cycle.

 
ATM kinase activity is also regulated by binding to MRE11 that enhances its ability to phosphorylate substrates in vitro (47). Given that ATM can be activated by ionizing radiation (IR) treatment in cells lacking NBS1 or BRCA1, but fails to be recruited to the DSB sites, it appears that the MRN complex enhances the accumulation of ATM at these sites (31–34). Taken together, ATM activity is likely regulated by two distinct events, one being the intermolecular autophosphorylation of ATM and dissociation of its homodimer induced by unknown chromatin changes, and the other, recruitment of the activated ATM to the substrate sites.

ATR was discovered in the human genome database as a gene with sequence homology to ATM and SpRad3, hence the name ATR (48). The gene encodes a protein of 303 kDa with a C-terminal kinase domain and regions of homology to other PIKK family members. Unlike ATM, an ATR deficiency in mice results in early embryonic death (49), and mutations causing a partial loss of its activity have been reported to be associated with the human autosomal recessive disorder, Seckel syndrome (50). As with ATM, ATR is capable of specifically phosphorylating serine or threonine residues in SQ/TQ sequences (51). Unlike ATM, however, there is no measurable change in the kinase activity of ATR, suggesting that it may be constitutively ready to phosphorylate substrates but that its functions may be largely dependent on its subcellular localization. In human cells, ATR exists in a stable complex with ATRIP, a potential regulatory partner (52,53). Mec1 and Rad3, the yeast homologs of ATR, also form a similar complex with Ddc2 and Rad26 (54,55), respectively. Given that RPA, an ssDNA-binding protein, stimulates in vitro binding of ATRIP to ssDNA (12), it is possible that the ATR–ATRIP complex is recruited at sites of DNA damage by means of the binding of ATRIP to RPA. However, the importance of RPA in the recruitment of ATR to ssDNA is still under question (53).

ATR must have some vital function in the normal cell cycle because it is essential for embryonic cell viability. The observation that RPA is involved in DNA replication (56) and a component of the DNA replication fork led to a model in which ATR–ATRIP localizes to sites of this fork, monitoring the progression of DNA replication. Once the active ATR is translocated to DNA replication foci, it can phosphorylate and activate Chk1. This model is consistent with the observation that Chk1 is also essential for embryonic cell viability (57,58). Recently, it has been reported that ATR regulates late origin firing of DNA replication (59). Therefore, ATR appears to be a multi-functional kinase that regulates several distinct events from S phase to M phase.

Checkpoint kinases Chk1 and Chk2
The checkpoint kinases Chk1 and Cds1(Chk2) were first identified in fission yeast as essential for cell-cycle arrest before mitosis in response to DNA damage or DNA replication blockage, respectively (60,61). These kinases were also identified in vertebrate cells based on their homology with yeast scChk1 and scRad53/spCds1 (62–66). Examination of mouse cells deficient in Chk1 revealed an essential role for this protein in DNA damage and the DNA replication checkpoint response (57,58). Chk1 is phosphorylated at Ser317/345 in response to DNA damage in both mammals and fission yeast (67,68). This phosphorylation is blocked in cells that lack the kinase ATR (58) and markedly inhibited in cells with a reduced amount of Rad17 (69) or lacking Hus1 (70), suggesting a conserved mechanism shared by mammals and yeasts in which sensor complexes associated with damaged DNA regulate the phosphorylation of Chk1. Whereas the Chk1 mutant of fission yeast is viable and remains apparently normal in the absence of DNA damage, Chk1-deficient mice die at an early embryonic stage of development with gross morphological abnormalities of their cell nuclei (57,58), suggesting that, similar to ATR, Chk1 plays a role at every point in the cell cycle. Consistent with this observation, a Chk1-deficiency resulted in the premature onset of mitosis through the dephosphorylation of Cdc2 at Tyr15 (71). In this respect, Chk1 has been shown to phosphorylate Cdc25-A, Cdc25-B and Cdc25-C, which downregulates their phosphatase activity through several distinct mechanisms (Figure 2). Recently, studies in the Xenopus system have demonstrated that Chk1 but not Chk2 specifically phosphorylates C-terminal portion of Cdc25 family members and inhibits their phosphatase activities toward cyclin–Cdk complex through interference of the interaction between Cdc25 and cyclin–Cdk. Since Chk1 but not Chk2 is indispensable for the cell-cycle arrest in response to genotoxic stresses, this phosphorylation might be important for checkpoint signals (see below).

In contrast to Chk1, Chk2 is dispensable for pre-natal development (72,73). Given that Chk2 is activated by phosphorylation of its threonine residue at 68 in an ATM-dependent manner in response to IR treatment (74), Chk2 is implicated in the DNA damage signaling pathway. This notion is further supported by a recent report that heterozygous germline mutations in the human Chk2 gene were found in a subset of patients with Li–Fraumeni syndrome without any mutation in their p53 gene (75). Biochemical analyses revealed that activated Chk2 phosphorylates Cdc25A at Ser123, Cdc25C on Ser216, BRCA1 at Ser988 and p53 at several sites, including Ser20 (76) (Figure 2). However, examination of Chk2-deficient mice and cells revealed that this enzyme functions mainly in p53-dependent apoptosis but not in G₂/M arrest upon DNA damage (73). Chk2-deficient mice are resistant to IR as a result of the preservation of splenic lymphocytes, thymocytes and neurons of the developing brain whose apoptosis is known to be p53 dependent. Although ATM–Chk2 function at the intra-S phase checkpoint upon DNA damage is considered to be important, because phosphorylation of Cdc25A triggers its ubiquitylation and degradation (77) (Figure 2), Chk2-deficient cells showed that it is dispensable for the intra-S phase checkpoint response. Thus, the function of Chk2 in cell-cycle arrest upon DNA damage remains questionable.

	Effector molecules

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p53
The p53 tumor suppressor protein plays a central role in the decision of a cell to undergo either cell-cycle arrest or apoptosis after diverse stresses, including DNA damage, hypoxia and the activation of oncogenes (78–80). The amount and transcriptional activity of p53 is regulated by post-translational modification, such as phosphorylation, sumorylation, neddation and acetylation (81). In normal cells, p53 protein levels are low owing to Mdm2-mediated ubiquitylation and degradation through the proteasome pathway. Mdm2 also regulates p53 activity by facilitating nuclear export (82). Upon DNA damage, p53 is phosphorylated at several sites in its transactivation domain, including at Ser15 and Ser20 (83). ATM and ATR phosphorylate p53 at Ser15 (45,46), which inhibits the interaction of p53 with Mdm2 (84), resulting in p53 stabilization. Mdm2 phosphorylation by ATM reduces its capability to promote nucleo–cytoplasmic shuttling and the subsequent degradation of p53 (85).

p53 is thought to be essential for G₁ arrest in response to DNA damage. The key transcriptional target of p53 is the p21 Cdk inhibitor (p21CKI) (86), which inhibits cyclin E–Cdk2 activity, thereby inhibiting G₁/S transition (87). p21CKI also binds to the cyclin D–Cdk4 complex and prevents it from phosphorylating Rb, thereby suppressing the RB/E2F pathway. Thus, the G₁ checkpoint signal targets two independent and critical tumour suppressor pathways that are most commonly deregulated in human cancers. However, p21-deficient cells are apparently normal in the initiation of G₁ arrest although the maintenance of G₁ arrest appears to be impaired, suggesting an alternative target should exist downstream of p53 (88).

Recent reports indicate a rapid decrease, independent of p53 status, in the abundance and activity of Cdc25A in response to DNA damage. This reduction in Cdc25A is triggered by phosphorylation of its Ser123 residue by Chk2 (77,89). However, Chk2-deficient cells show an apparently normal ability, at the very least, to initiate cell-cycle arrest at the G₁/S boundary upon DNA damage (73).

Recently, cyclin D1 degradation has also been reported to play an important role in the initiation of G₁ arrest upon DNA damage (90). The reduced cyclin D1 protein then decreases the amount of cyclin D1–Cdk4 complex, resulting in the redistribution of p21CKI to cyclin E–Cdk2 and the inhibition of cyclin E–Cdk2 (91,92). However, this checkpoint response is independent of ATM–p53. Taken together with the observation that triple knockout mice lacking cyclin D1, D2 and D3 show apparently normal cell-cycle control without significant defects in their checkpoint response (93), the main pathway by which p53 regulates the initiation of G₁ arrest in response to DNA damage remains elusive.

Cdc25 family of phosphatases
In humans, three phosphotyrosine phosphatases, Cdc25-A, Cdc25-B and Cdc25-C, dephosphorylate the Cdks that act on kinases directly to regulate cell cycle transitions. Studies in yeasts, Xenopus and mammals have demonstrated that phosphorylation of these Cdc25 proteins by Chk1 creates binding sites for 14-3-3 proteins and downregulates their phosphatase activities in several distinct ways, including by direct inhibition (65,94,95), excluding the proteins from the nucleus (96–98), and initiating their proteolytic degradation (77,99). For example, in the presence of DNA damage during S phase progression, activated ATR–Chk1 phosphorylates Cdc25A triggering its ubiquitination and degradation. The downregulated Cdc25A suppresses Cdk2 activation that blocks the loading of Cdc45 onto chromatin (100). Cdc45 is a protein required for the initiation of DNA replication through recruitment of DNA polymerase alpha into pre-replication complexes, resulting in the inhibition of new origin firing.

Initially, Cdc25C was thought to be the major effector of the G₂/M DNA damage checkpoint response. However, recent reports have revealed that both Cdc25C-deficient and Cdc25B-deficient cells have a normal G₂/M checkpoint (101,102), suggesting that Cdc25A is also the main effector at G₂/M checkpoints. Therefore, inactivation of Cdc25A leads to accumulation of phosphorylated Cdc2 at Tyr15 and mitotic arrest.

	Perspective

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Recent genetic analyses using mouse knockout technology or knock-down methods employing small interference RNA have revealed that the majority of DNA damage checkpoint pathways during S to M phase are well conserved between mammals and yeasts although the function of Chk2 at the DNA damage checkpoint is still unresolved. However, many other aspects of checkpoint signaling also remain unresolved. For example, initiation of the G₂/M checkpoint response may not be as simple as presented here. Mitogen activated phospho (MAP) kinases p38 (103) and p38 (104) have been implicated at the G₂/M checkpoint in response to DNA damage induced by IR or ultraviolet (UV), respectively. In addition, the Polo-like kinases (PLK) that are required for mitotic initiation upstream of Cdc25, PLK3 (105,106) and PLK1 (105,107), seem to be targeted by DNA-damage-induced mechanisms. S phase arrest defective kinase 1 (SAD1 kinase) also appears to be involved in DNA damage checkpoint activity induced by UV (108). Therefore, the interfacing of these signal transduction pathways deserves more study.

Involvement of DNA damage checkpoints in human carcinogenesis should also be re-evaluated. Mutations in ATM and Chk2 genes have been detected in human cancer susceptibility syndromes. However, the phenotypes of cells deficient in these genes are in complete contrast. ATM-deficient cells are hypersensitive to ionizing radiation (109), and Chk2-deficient cells are resistant (57,72). ATM is known to regulate other cellular responses to DNA damage including apoptosis and senescence as well as checkpoint signaling. In addition, unlike mice lacking ATM, Chk2-deficient mice are not significantly cancer-prone (57). BRCA1 and p53 are bona fide tumour suppressor genes, and mutation or deletion of these genes results in malignant transformation. However, their proteins also regulate other cellular responses, such as apoptosis and cellular senescence, suggesting that defects in cellular responses other than those involving checkpoints might contribute to malignant transformation in BRCA1- or p53-deficient cells. To clarify these issues, cross-talk between signaling pathways, such as those associated with checkpoints, cellular senescence, apoptosis and DNA repair, needs to be investigated.

	Notes

 
^* To whom correspondence should be addressed. Tel: +81 52 853 8144; Fax: +81 52 842 3955; Email: mkt-naka{at}med.nagoya-cu.ac.jp

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Received on March 25, 2005; revised on October 10, 2005; accepted on October 11, 2005.

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