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First published online January 21, 2009
doi: 10.1242/10.1242/jcs.035105
Cell Science at a Glance |
1 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA
2 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
* Author for correspondence (e-mail: zou.lee{at}mgh.harvard.edu)
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Introduction |
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 Top Introduction Sensing of DNA damageActivation of the ATR...Interplay between ATR and...Phosphorylation of ATR...Conclusions and perspectivesReferences |
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). ATM is primarily activated by DNA double-strand breaks (DSBs), whereas ATR responds to a much broader spectrum of DNA damage, including DSBs and many types of DNA damage that interfere with DNA replication (Cimprich and Cortez, 2008; Zou, 2007). In contrast to ATM, ATR has a crucial role in stabilizing the genome during DNA replication and is essential for cell survival (Brown and Baltimore, 2003). Here, we summarize the recent findings on ATR signaling in four areas: sensing of DNA damage; activation of the ATR kinase; interplay between ATR and ATM; and phosphorylation of ATR substrates.
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Sensing of DNA damage |
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TopIntroductionSensing of DNA damageActivation of the ATR...Interplay between ATR and...Phosphorylation of ATR...Conclusions and perspectivesReferences |
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; Walter and Newport, 2000). In addition, ssDNA gaps are induced by several types of DNA repair, such as nucleotide excision repair, mismatch repair and long-patch base excision repair (Friedberg, 2003; Lopes et al., 2006). ssDNA is also present at DSBs that have been trimmed by exo- or endonucleases through a process called resection (Lee et al., 1998). When ssDNA is generated at sites of DNA damage or at stalled DNA replication forks, it is always accompanied by junctions between ssDNA and dsDNA. Circular ssDNA that is annealed with primers, which possesses both ssDNA and ssDNA-dsDNA junctions, is sufficient to activate the ATR-mediated DNA-damage checkpoint response in Xenopus laevis egg extracts (MacDougall et al., 2007).
In all eukaryotes, ssDNA that is induced by DNA damage is first detected by replication protein A (RPA), which is an ssDNA-binding protein complex. ATR-interacting protein (ATRIP), which is the regulatory partner of ATR, binds directly to RPA-coated ssDNA (RPA-ssDNA) and thereby enables the ATR-ATRIP complex to localize to sites of DNA damage (Ball et al., 2005; Namiki and Zou, 2006; Zou and Elledge, 2003). The N-terminal RPA-interacting domains of human ATRIP and its Saccharomyces cerevisiae homolog Ddc2 are important for the recruitment of ATRIP and Ddc2 to sites of DNA damage (Ball et al., 2007; Ball et al., 2005; Zou and Elledge, 2003). Additional interactions between ATR-ATRIP and RPA, as well as the interactions between ATR-ATRIP and other proteins, might also contribute to the association of ATR-ATRIP with damaged DNA (Ball et al., 2005; Namiki and Zou, 2006; Yoshioka et al., 2006). The localization of ATR-ATRIP to sites of DNA damage, however, is by itself not sufficient to activate the DNA-damage-checkpoint response fully; instead, it requires the functions of additional ATR regulators, including RAD17, RAD9, RAD1 and HUS1. RAD17 is a protein that is structurally related to RFC1 (the largest subunit of the five-subunit replication complex RFC), and it forms an RFC-like complex with the four small subunits of RFC (RFC2-RFC5). By contrast, RAD9, RAD1 and HUS1 form a ring-shaped trimeric complex (the 9-1-1 complex) that resembles proliferating cell nuclear antigen (PCNA), a processivity factor for DNA polymerase. During DNA replication, RFC recognizes primer-template junctions and recruits PCNA onto DNA; similarly, during the DNA-damage response, the RAD17 complex recruits 9-1-1 complexes onto damaged DNA. Both RFC and the RAD17 complex require RPA for their function (Ellison and Stillman, 2003; Majka et al., 2006a; Zou et al., 2003). Unlike RFC, which specifically recognizes 3' dsDNA-ssDNA junctions, the RAD17 complex preferentially recruits 9-1-1 complexes to 5' dsDNA-ssDNA junctions, which are associated with resected DSBs and stressed replication forks (Ellison and Stillman, 2003; Majka et al., 2006a; Zou et al., 2003). The recognition of DNA damage by ATR-ATRIP and the RAD17 complex is largely independent (Kondo et al., 2001; Melo et al., 2001; Zou et al., 2002); in S. cerevisiae, colocalization of Ddc2 (which is homologous to ATRIP) and Ddc1 (which is homologous to RAD9) at artificial binding sites activates the DNA-damage checkpoint in the absence of DNA damage (Bonilla et al., 2008), suggesting that a crucial function of DNA damage in checkpoint activation is to bring ATR-ATRIP and the 9-1-1 complex together.
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Activation of the ATR kinase by TopBP1 |
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TopIntroductionSensing of DNA damageActivation of the ATR...Interplay between ATR and...Phosphorylation of ATR...Conclusions and perspectivesReferences |
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). Whether the 9-1-1 complex can stimulate ATR-ATRIP activity in other organisms is still unclear. In both human and Xenopus, DNA topoisomerase II binding protein 1 (TopBP1) stimulates the kinase activity of ATR-ATRIP even in the absence of DNA (Kumagai et al., 2006). Dpb11, the S. cerevisiae homolog of TopBP1, also stimulates the kinase activity of Mec1-Ddc2 (Mordes et al., 2008b; Navadgi-Patil and Burgers, 2008). Thus, TopBP1 is a direct and evolutionarily conserved stimulator of ATR-ATRIP.
How does TopBP1 interact with ATR-ATRIP? In both Xenopus and humans, the ATR-activating domain (AAD) of TopBP1 was mapped to a segment of the protein that lies between two BRCA1 C-terminal domains (BRCTs) – BRCT VI and BRCT VII (Kumagai et al., 2006). Inactivating mutations in the AAD diminished the DNA-damage-checkpoint response in Xenopus extracts, showing that the stimulation of ATR-ATRIP activity by TopBP1 is an important event during checkpoint activation (Kumagai et al., 2006). In humans, the AAD of TopBP1 interacts with the ATR-ATRIP complex via an internal region of ATRIP and the PIKK regulatory domain (PRD) near the C-terminus of ATR (Mordes et al., 2008a). The interaction between the AAD of TopBP1 and the PRD of ATR, as well as the interaction between the AAD of TopBP1 and ATRIP, are important for the stimulation of ATR by the AAD (Mordes et al., 2008a).
How is the stimulation of ATR-ATRIP by TopBP1 regulated by DNA damage? In humans and S. cerevisiae, TopBP1 and Dpb11 were found to interact with RAD9 and Ddc1, respectively (Makiniemi et al., 2001; Wang and Elledge, 2002). Subsequent studies have shown that both human and Xenopus TopBP1 associate with the C-terminus of RAD9 through the BRCT I and BRCT II domains of TopBP1 and phosphoserine 387 of RAD9 (Delacroix et al., 2007; Lee et al., 2007). This interaction between RAD9 and TopBP1, which is required for checkpoint activation in Xenopus extracts and chicken cells, might provide a means to recruit TopBP1 to sites of DNA damage. Nonetheless, the phosphorylation of certain ATR substrates, such as RAD1, is dependent on TopBP1 but not on the C-terminus of RAD9 in Xenopus extracts (Lupardus and Cimprich, 2006), which suggests that TopBP1 can be regulated by DNA damage through alternative mechanisms that are independent of the C-terminus of RAD9. Fusion of the AAD of TopBP1 with PCNA or histone H2B directly localizes the domain to chromatin and bypasses the requirement for RAD17 for activation of the DNA-damage checkpoint, which indicates that a crucial function of RAD17 and 9-1-1 in ATR activation is to bring TopBP1 to sites of DNA damage (Delacroix et al., 2007).
In addition to stimulating the kinase activity of ATR, TopBP1 is a substrate of ATR and ATM. Serine 1131 of Xenopus TopBP1 is phosphorylated by ATR in response to replication inhibition, or by ATM in the presence of the synthetic DNA structures that are generated in the presence of poly deoxyadenine (poly-dA) and poly deoxythymidine (poly-dT) (Hashimoto et al., 2006; Yoo et al., 2007). The phosphorylation of serine 1131 enhances the interaction between TopBP1 and ATR-ATRIP, which suggests that TopBP1 phosphorylation promotes a feed-forward signaling loop that amplifies ATR-mediated signals (Yoo et al., 2007).
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Interplay between ATR and ATM |
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TopIntroductionSensing of DNA damageActivation of the ATR...Interplay between ATR and...Phosphorylation of ATR...Conclusions and perspectivesReferences |
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; Myers and Cortez, 2006). When they are generated in cells, DSBs are recognized by a protein complex that comprises meiotic recombination protein 11 (MRE11), RAD50 and Nijmegen breakage syndrome protein 1 (NBS1). The MRN11-RAD50-NBS1 (MRN) complex recruits and stimulates ATM, and is crucial for the function of ATM at DSBs (Berkovich et al., 2007; Falck et al., 2005; Kitagawa et al., 2004; Lee and Paull, 2005; You et al., 2005). ATM is rapidly activated by DSBs throughout the cell cycle, whereas ATR is activated more slowly, and predominantly during the S and G2 phases (see below) (Jazayeri et al., 2006). Thus, the activation of ATM by DSBs is necessary, but not sufficient, to activate ATR.
The function of ATM in ATR activation is, at least in part, attributable to its role in DSB resection. ATM is required for the resection of DSBs by exo- and endonucleases, which generates long stretches of ssDNA adjacent to the breaks (Jazayeri et al., 2006). The exo- and endonucleases involved in DSB resection include the MRN complex (an exo- and endonuclease), CtIP (an endonuclease and an activator of the exonuclease activity of MRN) and EXO1 (an exonuclease) (Buis et al., 2008; Sartori et al., 2007; Schaetzlein et al., 2007). In addition to these nucleases, the DNA helicase BLM is implicated in DSB resection (Gravel et al., 2008). Recent studies have suggested that the resection of DSBs occurs in a two-step manner (Mimitou and Symington, 2008; Zhu et al., 2008). During the initial stage, the MRN complex and CtIP function together to generate short stretches of ssDNA at DNA ends. Subsequently, the DSBs that have been processed by MRN and CtIP are further resected by two redundant mechanisms involving EXO1 and BLM, respectively. In S. cerevisiae, Dna2, which possesses both DNA helicase and endonuclease activities, might function with the BLM homolog Sgs1 during the second stage of resection (Mimitou and Symington, 2008; Zhu et al., 2008). Most, if not all, of the factors involved in the two-step DSB resection are required for efficient activation of ATR, suggesting that long stretches of ssDNA at DSBs are needed for ATR activation. Although ATM is clearly required for DSB resection, the precise function of ATM is still unknown.
In addition to ATM, the cyclin-dependent kinases (CDKs) are important regulators of DSB resection (Ira et al., 2004; Jazayeri et al., 2006; Zierhut and Diffley, 2008). In S. cerevisiae, the phosphorylation of Sae2 (the functional homolog of CtIP) by CDKs is needed for efficient DSB resection (Huertas et al., 2008). The activation of CDKs during the S and G2 phases of the cell cycle might facilitate ATR activation during these periods. Deletion of Ku70 and Ku80, which form a protein complex that inhibits the binding and function of the MRN complex at DSBs, enables DSB resection even in G1 (Clerici et al., 2008). Thus, CDKs might promote DSB resection by alleviating the inhibitory effects of Ku70 and Ku80 on this process.
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Phosphorylation of ATR substrates |
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TopIntroductionSensing of DNA damageActivation of the ATR...Interplay between ATR and...Phosphorylation of ATR...Conclusions and perspectivesReferences |
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). Chk1 is not only important for the checkpoint response during S phase, but is also crucial for the stability of DNA replication forks. In response to DNA damage, Chk1 is phosphorylated by ATR at multiple sites, which stimulates the kinase activity of Chk1 and releases it from chromatin. Activated Chk1 phosphorylates numerous substrates including Cdc25A and Cdc25C, which are involved in cell-cycle arrest at the G1-S and G2-M transitions, respectively.
The phosphorylation of Chk1 by ATR is mediated by claspin, which is a possible component of DNA replication forks (Osborn and Elledge, 2003). Even in the absence of DNA damage, claspin and Chk1 stabilize each other (Chini et al., 2006; Mamely et al., 2006; Yang et al., 2008). In response to DNA damage, claspin is phosphorylated by ATR and by an unidentified kinase in an ATR-dependent manner (Kumagai and Dunphy, 2003; Yoo et al., 2006). The ATR-mediated phosphorylation of claspin promotes the phosphorylation of Chk1 by ATR and might directly stimulate the kinase activity of Chk1 (Kumagai et al., 2004). The level of claspin is tightly regulated during the cell cycle – it is degraded in the G2 and M phases by the Skp1–Cullin1–F-box (SCF) ubiquitin ligase through a Polo-like kinase 1 (Plk1)-regulated mechanism (Mailand et al., 2006; Peschiaroli et al., 2006) and is degraded in G1 by the anaphase-promoting complex (APC) (Bassermann et al., 2008). In response to DNA damage, the degradation of claspin in G2 is disrupted (Bassermann et al., 2008). The ability of claspin to accumulate during the S and G2 phases ensures efficient Chk1 activation in this cell-cycle window if DNA is damaged. The claspin-mediated phosphorylation of Chk1 provides an example of how the phosphorylation of ATR substrates can be regulated at multiple levels.
Several recent large-scale proteomic studies have identified hundreds of proteins that are phosphorylated at [S/T]Q sites by ATM or ATR (Matsuoka et al., 2007; Mu et al., 2007; Smolka et al., 2007; Stokes et al., 2007). Among these substrates, some were shown to be preferentially phosphorylated by ATR. Given that ATM is required for the activation of ATR by DSBs, some of the substrates might be phosphorylated by ATR in an ATM-dependent manner. Many ATM or ATR substrates are involved in DNA-damage signaling, DNA replication and DNA repair. In addition, many ATM or ATR substrates function in protein modification (such as ubiquitylation), transcriptional regulation, developmental processes, cell structure, mobility, proliferation and differentiation. These studies reveal that ATM and ATR regulate a much broader spectrum of cellular processes than was previously appreciated.
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Conclusions and perspectives |
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TopIntroductionSensing of DNA damageActivation of the ATR...Interplay between ATR and...Phosphorylation of ATR...Conclusions and perspectivesReferences |
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Despite the identification of many ATR regulators, little is known about the biochemical details of ATR activation. We also know little about the organization of the ATR pathway in the contexts of DNA replication and various types of DNA repair. The key substrates of ATR that mediate the relevant cellular processes, such as the stabilization of stalled replication forks, remain to be identified. The recent proteomic studies discussed above have extended the network of cellular processes that might be orchestrated by ATR, and the functions of ATR in regulating and coordinating these processes await further investigation. Finally, because ATR is an essential protein, its functions in animals have only been explored to a limited degree (Ruzankina et al., 2007). We anticipate that combined biochemical, cell-biological and genomic studies on ATR will attest to its role as a central safeguard of the genome.
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Footnotes |
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References |
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TopIntroductionSensing of DNA damageActivation of the ATR...Interplay between ATR and...Phosphorylation of ATR...Conclusions and perspectivesReferences |
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Ball, H. L., Myers, J. S. and Cortez, D. (2005). ATRIP binding to replication protein A-single-stranded DNA promotes ATR-ATRIP localization but is dispensable for Chk1 phosphorylation. Mol. Biol. Cell 16, 2372-2381.
Ball, H. L., Ehrhardt, M. R., Mordes, D. A., Glick, G. G., Chazin, W. J. and Cortez, D. (2007). Function of a conserved checkpoint recruitment domain in ATRIP proteins. Mol. Cell. Biol. 27, 3367-3377.
Bartek, J. and Lukas, J. (2003). Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3, 421-429.[CrossRef][Medline]
Bassermann, F., Frescas, D., Guardavaccaro, D., Busino, L., Peschiaroli, A. and Pagano, M. (2008). The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell 134, 256-267.
Berkovich, E., Monnat, R. J., Jr and Kastan, M. B. (2007). Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nat. Cell Biol. 9, 683-690.[CrossRef][Medline]
Bonilla, C. Y., Melo, J. A. and Toczyski, D. P. (2008). Colocalization of sensors is sufficient to activate the DNA damage checkpoint in the absence of damage. Mol. Cell 30, 267-276.[CrossRef][Medline]
Brown, E. J. and Baltimore, D. (2003). Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 17, 615-628.
Buis, J., Wu, Y., Deng, Y., Leddon, J., Westfield, G., Eckersdorff, M., Sekiguchi, J. M., Chang, S. and Ferguson, D. O. (2008). Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 135, 85-96.[CrossRef][Medline]
Byun, T. S., Pacek, M., Yee, M. C., Walter, J. C. and Cimprich, K. A. (2005). Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 19, 1040-1052.
Chini, C. C., Wood, J. and Chen, J. (2006). Chk1 is required to maintain claspin stability. Oncogene 25, 4165-4171.[CrossRef][Medline]
Cimprich, K. A. and Cortez, D. (2008). ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell. Biol. 9, 616-627.[CrossRef][Medline]
Clerici, M., Mantiero, D., Guerini, I., Lucchini, G. and Longhese, M. P. (2008). The Yku70-Yku80 complex contributes to regulate double-strand break processing and checkpoint activation during the cell cycle. EMBO Rep. 9, 810-818.[CrossRef][Medline]
Delacroix, S., Wagner, J. M., Kobayashi, M., Yamamoto, K. and Karnitz, L. M. (2007). The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1. Genes Dev. 21, 1472-1477.
Ellison, V. and Stillman, B. (2003). Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5' recessed DNA. PLoS Biol. 1, E33.[Medline]
Falck, J., Coates, J. and Jackson, S. P. (2005). Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605-611.[CrossRef][Medline]
Friedberg, E. C. (2003). DNA damage and repair. Nature 421, 436-440.[CrossRef][Medline]
Gravel, S., Chapman, J. R., Magill, C. and Jackson, S. P. (2008). DNA helicases Sgs1 and BLM promote DNA double-strand break resection. Genes Dev. 22, 2767-2772.
Harper, J. W. and Elledge, S. J. (2007). The DNA damage response: ten years after. Mol. Cell 28, 739-745.[Medline]
Hashimoto, Y., Tsujimura, T., Sugino, A. and Takisawa, H. (2006). The phosphorylated C-terminal domain of Xenopus Cut5 directly mediates ATR-dependent activation of Chk1. Genes Cells 11, 993-1007.
Huertas, P., Cortes-Ledesma, F., Sartori, A. A., Aguilera, A. and Jackson, S. P. (2008). CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455, 689-692.[CrossRef][Medline]
Ira, G., Pellicioli, A., Balijja, A., Wang, X., Fiorani, S., Carotenuto, W., Liberi, G., Bressan, D., Wan, L., Hollingsworth, N. M. et al. (2004). DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431, 1011-1017.[CrossRef][Medline]
Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G. C., Lukas, J. and Jackson, S. P. (2006). ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat. Cell Biol. 8, 37-45.[CrossRef][Medline]
Kitagawa, R., Bakkenist, C. J., McKinnon, P. J. and Kastan, M. B. (2004). Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway. Genes Dev. 18, 1423-1438.
Kondo, T., Wakayama, T., Naiki, T., Matsumoto, K. and Sugimoto, K. (2001). Recruitment of Mec1 and Ddc1 checkpoint proteins to double-strand breaks through distinct mechanisms. Science 294, 867-870.
Kumagai, A. and Dunphy, W. G. (2003). Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1. Nat. Cell Biol. 5, 161-165.[CrossRef][Medline]
Kumagai, A., Kim, S. M. and Dunphy, W. G. (2004). Claspin and the activated form of ATR-ATRIP collaborate in the activation of Chk1. J. Biol. Chem. 279, 49599-49608.
Kumagai, A., Lee, J., Yoo, H. Y. and Dunphy, W. G. (2006). TopBP1 activates the ATR-ATRIP complex. Cell 124, 943-955.[CrossRef][Medline]
Lee, J. H. and Paull, T. T. (2005). ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308, 551-554.
Lee, J., Kumagai, A. and Dunphy, W. G. (2007). The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. J. Biol. Chem. 282, 28036-28044.
Lee, S. E., Moore, J. K., Holmes, A., Umezu, K., Kolodner, R. D. and Haber, J. E. (1998). Saccharomyces Ku70, mre11/rad50 and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 94, 399-409.[CrossRef][Medline]
Lopes, M., Foiani, M. and Sogo, J. M. (2006). Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol. Cell 21, 15-27.[CrossRef][Medline]
Lupardus, P. J. and Cimprich, K. A. (2006). Phosphorylation of Xenopus Rad1 and Hus1 defines a readout for ATR activation that is independent of Claspin and the Rad9 carboxy terminus. Mol. Biol. Cell 17, 1559-1569.
MacDougall, C. A., Byun, T. S., Van, C., Yee, M. C. and Cimprich, K. A. (2007). The structural determinants of checkpoint activation. Genes Dev. 21, 898-903.
Mailand, N., Bekker-Jensen, S., Bartek, J. and Lukas, J. (2006). Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress. Mol. Cell 23, 307-318.[CrossRef][Medline]
Majka, J., Binz, S. K., Wold, M. S. and Burgers, P. M. (2006a). Replication protein A directs loading of the DNA damage checkpoint clamp to 5'-DNA junctions. J. Biol. Chem. 281, 27855-27861.
Majka, J., Niedziela-Majka, A. and Burgers, P. M. (2006b). The checkpoint clamp activates Mec1 kinase during initiation of the DNA damage checkpoint. Mol. Cell 24, 891-901.[CrossRef][Medline]
Makiniemi, M., Hillukkala, T., Tuusa, J., Reini, K., Vaara, M., Huang, D., Pospiech, H., Majuri, I., Westerling, T., Makela, T. P. et al. (2001). BRCT domain-containing protein TopBP1 functions in DNA replication and damage response. J. Biol. Chem. 276, 30399-30406.
Mamely, I., van Vugt, M. A., Smits, V. A., Semple, J. I., Lemmens, B., Perrakis, A., Medema, R. H. and Freire, R. (2006). Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr. Biol. 16, 1950-1955.[CrossRef][Medline]
Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R., 3rd, Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y. et al. (2007). ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160-1166.
Melo, J. A., Cohen, J. and Toczyski, D. P. (2001). Two checkpoint complexes are independently recruited to sites of DNA damage in vivo. Genes Dev. 15, 2809-2821.
Mimitou, E. P. and Symington, L. S. (2008). Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455, 770-774.[CrossRef][Medline]
Mordes, D. A., Glick, G. G., Zhao, R. and Cortez, D. (2008a). TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes Dev. 22, 1478-1489.
Mordes, D. A., Nam, E. A. and Cortez, D. (2008b). Dpb11 activates the Mec1-Ddc2 complex. Proc. Natl. Acad. Sci. USA 105, 18730-18734.
Mu, J. J., Wang, Y., Luo, H., Leng, M., Zhang, J., Yang, T., Besusso, D., Jung, S. Y. and Qin, J. (2007). A proteomic analysis of ataxia telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) substrates identifies the ubiquitin-proteasome system as a regulator for DNA damage checkpoints. J. Biol. Chem. 282, 17330-17334.
Myers, J. S. and Cortez, D. (2006). Rapid activation of ATR by ionizing radiation requires ATM and Mre11. J. Biol. Chem. 281, 9346-9350.
Namiki, Y. and Zou, L. (2006). ATRIP associates with replication protein A-coated ssDNA through multiple interactions. Proc. Natl. Acad. Sci. USA 103, 580-585.
Navadgi-Patil, V. M. and Burgers, P. M. (2008). Yeast DNA replication protein Dpb11 activates the Mec1/ATR checkpoint kinase. J. Biol. Chem. 283, 35853-35859.
Osborn, A. J. and Elledge, S. J. (2003). Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53. Genes Dev. 17, 1755-1767.
Peschiaroli, A., Dorrello, N. V., Guardavaccaro, D., Venere, M., Halazonetis, T., Sherman, N. E. and Pagano, M. (2006). SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response. Mol. Cell 23, 319-329.[CrossRef][Medline]
Ruzankina, Y., Pinzon-Guzman, C., Asare, A., Ong, T., Pontano, L., Cotsarelis, G., Zediak, V. P., Velez, M., Bhandoola, A. and Brown, E. J. (2007). Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell 1, 113-126.[CrossRef][Medline]
Sartori, A. A., Lukas, C., Coates, J., Mistrik, M., Fu, S., Bartek, J., Baer, R., Lukas, J. and Jackson, S. P. (2007). Human CtIP promotes DNA end resection. Nature 450, 509-514.[CrossRef][Medline]
Schaetzlein, S., Kodandaramireddy, N. R., Ju, Z., Lechel, A., Stepczynska, A., Lilli, D. R., Clark, A. B., Rudolph, C., Kuhnel, F., Wei, K. et al. (2007). Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice. Cell 130, 863-877.[CrossRef][Medline]
Smolka, M. B., Albuquerque, C. P., Chen, S. H. and Zhou, H. (2007). Proteome-wide identification of in vivo targets of DNA damage checkpoint kinases. Proc. Natl. Acad. Sci. USA 104, 10364-10369.
Stokes, M. P., Rush, J., Macneill, J., Ren, J. M., Sprott, K., Nardone, J., Yang, V., Beausoleil, S. A., Gygi, S. P., Livingstone, M. et al. (2007). Profiling of UV-induced ATM/ATR signaling pathways. Proc. Natl. Acad. Sci. USA 104, 19855-19860.
Walter, J. and Newport, J. (2000). Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha. Mol. Cell 5, 617-627.[CrossRef][Medline]
Wang, H. and Elledge, S. J. (2002). Genetic and physical interactions between DPB11 and DDC1 in the yeast DNA damage response pathway. Genetics 160, 1295-1304.
Yang, X. H., Shiotani, B., Classon, M. and Zou, L. (2008). Chk1 and Claspin potentiate PCNA ubiquitination. Genes Dev. 22, 1147-1152.
Yoo, H. Y., Jeong, S. Y. and Dunphy, W. G. (2006). Site-specific phosphorylation of a checkpoint mediator protein controls its responses to different DNA structures. Genes Dev. 20, 772-783.
Yoo, H. Y., Kumagai, A., Shevchenko, A. and Dunphy, W. G. (2007). Ataxia-telangiectasia mutated (ATM)-dependent activation of ATR occurs through phosphorylation of TopBP1 by ATM. J. Biol. Chem. 282, 17501-17506.
Yoshioka, K., Yoshioka, Y. and Hsieh, P. (2006). ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts. Mol. Cell 22, 501-510.[CrossRef][Medline]
You, Z., Chahwan, C., Bailis, J., Hunter, T. and Russell, P. (2005). ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol. Cell. Biol. 25, 5363-5379.
Zhu, Z., Chung, W. H., Shim, E. Y., Lee, S. E. and Ira, G. (2008). Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134, 981-994.[CrossRef][Medline]
Zierhut, C. and Diffley, J. F. (2008). Break dosage, cell cycle stage and DNA replication influence DNA double strand break response. EMBO J. 27, 1875-1885.[CrossRef][Medline]
Zou, L. (2007). Single- and double-stranded DNA: building a trigger of ATR-mediated DNA damage response. Genes Dev. 21, 879-885.
Zou, L. and Elledge, S. J. (2003). Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 1542-1548.
Zou, L., Cortez, D. and Elledge, S. J. (2002). Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes Dev. 16, 198-208.
Zou, L., Liu, D. and Elledge, S. J. (2003). Replication protein A-mediated recruitment and activation of Rad17 complexes. Proc. Natl. Acad. Sci. USA 100, 13827-13832.
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