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Molecular and Cellular Biology, July 2004, p. 6215-6230, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6215-6230.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Histone H2A Phosphorylation Controls Crb2 Recruitment at DNA Breaks, Maintains Checkpoint Arrest, and Influences DNA Repair in Fission Yeast{dagger}

Toru M. Nakamura,1* Li-Lin Du,1 Christophe Redon,2 and Paul Russell1,3*

Departments of Molecular Biology,1 Cell Biology, The Scripps Research Institute, La Jolla, California 92037,3 Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922

Received 17 March 2004/ Returned for modification 20 April 2004/ Accepted 26 April 2004

Mammalian ATR and ATM checkpoint kinases modulate chromatin structures near DNA breaks by phosphorylating a serine residue in the carboxy-terminal tail SQE motif of histone H2AX. Histone H2A is similarly regulated in Saccharomyces cerevisiae. The phosphorylated forms of H2AX and H2A, known as {gamma}-H2AX and {gamma}-H2A, are thought to be important for DNA repair, although their evolutionarily conserved roles are unknown. Here, we investigate {gamma}-H2A in the fission yeast Schizosaccharomyces pombe. We show that formation of {gamma}-H2A redundantly requires the ATR/ATM-related kinases Rad3 and Tel1. Mutation of the SQE motif to AQE (H2A-AQE) in the two histone H2A genes caused sensitivity to a wide range of genotoxic agents, increased spontaneous DNA damage, and impaired checkpoint maintenance. The H2A-AQE mutations displayed a striking synergistic interaction with rad22{Delta} (Rad52 homolog) in ionizing radiation (IR) survival. These phenotypes correlated with defective phosphorylation of the checkpoint proteins Crb2 and Chk1 and a failure to recruit large amounts of Crb2 to damaged DNA. Surprisingly, the H2A-AQE mutations substantially suppressed the IR hypersensitivity of crb2{Delta} cells by a mechanism that required the RecQ-like DNA helicase Rqh1. We propose that {gamma}-H2A modulates checkpoint and DNA repair through large-scale recruitment of Crb2 to damaged DNA. This function correlates with evidence that {gamma}-H2AX regulates recruitment of several BRCA1 carboxyl terminus domain-containing proteins (NBS1, 53BP1, MDC1/NFBD1, and BRCA1) in mammals.

* Corresponding author. Mailing address: Department of Molecular Biology, The Scripps Research Institute, MB3, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone for T. M. Nakamura: (858) 784-2823. Fax: (858) 784-2265. E-mail: nakamut{at}scripps.edu. Phone for Paul Russell: (858) 784-8273. Fax: (858) 784-2265. E-mail: prussel{at}scripps.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2004, p. 6215-6230, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6215-6230.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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