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Molecular and Cellular Biology, December 2005, p. 10721-10730, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.10721-10730.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cooperative Control of Crb2 by ATM Family and Cdc2 Kinases Is Essential for the DNA Damage Checkpoint in Fission Yeast

Toru M. Nakamura,1,3* Bettina A. Moser,1,3 Li-Lin Du,1 and Paul Russell1,2*

Departments of Molecular Biology,1 Cell Biology, The Scripps Research Institute, La Jolla, California 92037,2 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 606073

Received 29 August 2005/ Returned for modification 19 September 2005/ Accepted 26 September 2005

The cellular responses to double-stranded breaks (DSBs) typically involve the extensive accumulation of checkpoint proteins in chromatin surrounding the damaged DNA. One well-characterized example involves the checkpoint protein Crb2 in the fission yeast Schizosaccharomyces pombe. The accumulation of Crb2 at DSBs requires the C-terminal phosphorylation of histone H2A (known as {gamma}-H2A) by ATM family kinases in chromatin surrounding the break. It also requires the constitutive methylation of histone H4 on lysine-20 (K20). Interestingly, neither type of histone modification is essential for the Crb2-dependent checkpoint response. However, H4-K20 methylation is essential in a crb2-T215A strain that lacks a cyclin-dependent kinase phosphorylation site in Crb2. Here we explain this genetic interaction by describing a previously overlooked effect of the crb2-T215A mutation. We show that crb2-T215A cells are able to initiate but not sustain a checkpoint response. We also report that {gamma}-H2A is essential for the DNA damage checkpoint in crb2-T215A cells. Importantly, we show that inactivation of Cdc2 in {gamma}-H2A-defective cells impairs Crb2-dependent signaling to the checkpoint kinase Chk1. These findings demonstrate that full Crb2 activity requires phosphorylation of threonine-215 by Cdc2. This regulation of Crb2 is independent of the histone modifications that are required for the hyperaccumulation of Crb2 at DSBs.

* Corresponding author. Mailing address for Paul Russell: Department of Molecular Biology, MB3, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-8273. Fax: (858) 784-2265. E-mail: prussell{at}scripps.edu. Mailing address for Toru M. Nakamura: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S. Ashland Ave. M/C669, Chicago, IL 60607. Phone: (312) 996-1988. Fax: (312) 413-0353. E-mail: nakamut{at}uic.edu.

Molecular and Cellular Biology, December 2005, p. 10721-10730, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.10721-10730.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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