A phosphatase complex that dephosphorylates γH2AX regulates DNA damage checkpoint recovery

Michael-Christopher Keogh, Jung-Ae Kim, Michael Downey, Jeffrey Fillingham, Dipanjan Chowdhury, Jacob C. Harrison, Megumi Onishi, Nira Datta, Sarah Galicia, Andrew Emili, Judy Lieberman, Xuetong Shen, Stephen Buratowski, James E. Haber, Daniel Durocher (), Jack F. Greenblatt () and Nevan J. Krogan
Additional contact information
Michael-Christopher Keogh: Department of Biological Chemistry and Molecular Pharmacology
Jung-Ae Kim: Brandeis University
Michael Downey: Departments of Medical Genetics and Microbiology
Jeffrey Fillingham: Departments of Medical Genetics and Microbiology
Dipanjan Chowdhury: Department of Pediatrics
Jacob C. Harrison: Brandeis University
Megumi Onishi: Harvard Medical School
Nira Datta: Departments of Medical Genetics and Microbiology
Sarah Galicia: Mount Sinai Hospital
Andrew Emili: Departments of Medical Genetics and Microbiology
Judy Lieberman: Department of Pediatrics
Xuetong Shen: MD Anderson Cancer Center
Stephen Buratowski: Department of Biological Chemistry and Molecular Pharmacology
James E. Haber: Brandeis University
Daniel Durocher: Departments of Medical Genetics and Microbiology
Jack F. Greenblatt: Departments of Medical Genetics and Microbiology
Nevan J. Krogan: Departments of Medical Genetics and Microbiology

Nature, 2006, vol. 439, issue 7075, 497-501

Abstract: Abstract One of the earliest marks of a double-strand break (DSB) in eukaryotes is serine phosphorylation of the histone variant H2AX at the carboxy-terminal SQE motif to create γH2AX-containing nucleosomes1. Budding-yeast histone H2A is phosphorylated in a similar manner by the checkpoint kinases Tel1 and Mec1 (ref. 2; orthologous to mammalian ATM and ATR, respectively) over a 50-kilobase region surrounding the DSB3. This modification is important for recruiting numerous DSB-recognition and repair factors to the break site, including DNA damage checkpoint proteins4,5, chromatin remodellers6 and cohesins7,8. Multiple mechanisms for eliminating γH2AX as DNA repair completes are possible, including removal by histone exchange followed potentially by degradation, or, alternatively, dephosphorylation. Here we describe a three-protein complex (HTP-C, for histone H2A phosphatase complex) containing the phosphatase Pph3 that regulates the phosphorylation status of γH2AX in vivo and efficiently dephosphorylates γH2AX in vitro. γH2AX is lost from chromatin surrounding a DSB independently of the HTP-C, indicating that the phosphatase targets γH2AX after its displacement from DNA. The dephosphorylation of γH2AX by the HTP-C is necessary for efficient recovery from the DNA damage checkpoint.

Date: 2006
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DOI: 10.1038/nature04384

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