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A phosphatase complex that dephosphorylates γH2AX regulates DNA damage checkpoint recovery

Author

Listed:
  • Michael-Christopher Keogh

    (Department of Biological Chemistry and Molecular Pharmacology)

  • Jung-Ae Kim

    (Brandeis University)

  • Michael Downey

    (Departments of Medical Genetics and Microbiology
    Mount Sinai Hospital)

  • Jeffrey Fillingham

    (Departments of Medical Genetics and Microbiology
    University of Toronto)

  • Dipanjan Chowdhury

    (Department of Pediatrics
    CBR Institute for Biomedical Research)

  • Jacob C. Harrison

    (Brandeis University)

  • Megumi Onishi

    (Harvard Medical School)

  • Nira Datta

    (Departments of Medical Genetics and Microbiology
    University of Toronto)

  • Sarah Galicia

    (Mount Sinai Hospital)

  • Andrew Emili

    (Departments of Medical Genetics and Microbiology
    University of Toronto)

  • Judy Lieberman

    (Department of Pediatrics
    CBR Institute for Biomedical Research)

  • 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
    Mount Sinai Hospital)

  • Jack F. Greenblatt

    (Departments of Medical Genetics and Microbiology
    University of Toronto)

  • Nevan J. Krogan

    (Departments of Medical Genetics and Microbiology
    University of Toronto
    UCSF)

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.

Suggested Citation

  • 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 & Xu, 2006. "A phosphatase complex that dephosphorylates γH2AX regulates DNA damage checkpoint recovery," Nature, Nature, vol. 439(7075), pages 497-501, January.
    • Handle: RePEc:nat:nature:v:439:y:2006:i:7075:d:10.1038_nature04384
    DOI: 10.1038/nature04384
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    Cited by:

    1. Gongwang Yu & Yao Liu & Zizhang Li & Shuyun Deng & Zhuoxing Wu & Xiaoyu Zhang & Wenbo Chen & Junnan Yang & Xiaoshu Chen & Jian-Rong Yang, 2023. "Genome-wide probing of eukaryotic nascent RNA structure elucidates cotranscriptional folding and its antimutagenic effect," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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