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RESEARCH COMMUNICATION
1 Department of Molecular Pharmacology and Experimental Therapeutics, Department of Radiation Oncology, and the Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA; 2 Department of Molecular Pathology and Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
DNA replication stress triggers the activation of Checkpoint Kinase 1 (Chk1) in a pathway that requires the independent chromatin loading of the ATRIP–ATR (ATR-interacting protein/ATM [ataxia-telangiectasia mutated]–Rad3-related kinase) complex and the Rad9–Hus1–Rad1 (9–1–1) clamp. We show that Rad9’s role in Chk1 activation is to bind TopBP1, which stimulates ATR-mediated Chk1 phosphorylation via TopBP1’s activation domain (AD), a domain that binds and activates ATR. Notably, fusion of the AD to proliferating cell nuclear antigen (PCNA) or histone H2B bypasses the requirement for the 9–1–1 clamp, indicating that the 9–1–1 clamp’s primary role in activating Chk1 is to localize the AD to a stalled replication fork.
[Keywords: Checkpoint; replication; Rad9; ATR; TopBP1; Chk1]
Received February 28, 2007; revised version accepted April 19, 2007.
E-MAIL karnitz.larry{at}mayo.edu; FAX (507) 284-3906.
Supplemental material is available at http://www.genesdev.org.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1547007
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