Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 27, Issue 17, Pages 6053-6067Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00532-07
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Funding
- NCI NIH HHS [R01 CA102361, CA102361] Funding Source: Medline
- NCRR NIH HHS [P41 RR011823] Funding Source: Medline
- NIDDK NIH HHS [5 T32 DK007022, T32 DK007022] Funding Source: Medline
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The Mre11/Rad50/Nbs1 complex (MRN) plays an essential role in the S-phase checkpoint. Cells derived from patients with Nijmegen breakage syndrome and ataxia telangiectasia-like disorder undergo radioresistant DNA synthesis (RDS), failing to suppress DNA replication in response to ionizing radiation (IR). How MRN affects DNA replication to control the S-phase checkpoint, however, remains unclear. We demonstrate that MRN directly interacts with replication protein A (RPA) in unperturbed cells and that the interaction is regulated by cyclin-dependent kinases. We also show that this interaction is needed for MRN to correctly localize to replication centers. Abolishing the interaction of Mre11 with RPA leads to pronounced RDS without affecting phosphorylation of Nbs1 or SMC1 following IR. Moreover, MRN is recruited to sites at or adjacent to replication origins by RPA and acts there to inhibit new origin firing upon IR. These studies suggest a direct role of MRN at origin-proximal sites to control DNA replication initiation in response to DNA damage, thereby providing an important mechanism underlying the intra-S-phase checkpoint in mammalian cells.
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