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Genes Dev. 2016 Apr 15;30(8):946-59. doi: 10.1101/gad.271841.115.

USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response.

Author information

1
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA;
2
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
3
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA; Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA;
4
Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA;
5
Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

Abstract

Dynamic regulation of RNF168-mediated ubiquitylation of histone H2A Lys13,15 (H2AK13,15ub) at DNA double-strand breaks (DSBs) is crucial for preventing aberrant DNA repair and maintaining genome stability. However, it remains unclear which deubiquitylating enzyme (DUB) removes H2AK13,15ub. Here we show that USP51, a previously uncharacterized DUB, deubiquitylates H2AK13,15ub and regulates DNA damage response. USP51 depletion results in increased spontaneous DNA damage foci and elevated levels of H2AK15ub and impairs DNA damage response. USP51 overexpression suppresses the formation of ionizing radiation-induced 53BP1 and BRCA1 but not RNF168 foci, suggesting that USP51 functions downstream from RNF168 in DNA damage response. In vitro, USP51 binds to H2A-H2B directly and deubiquitylates H2AK13,15ub. In cells, USP51 is recruited to chromatin after DNA damage and regulates the dynamic assembly/disassembly of 53BP1 and BRCA1 foci. These results show that USP51 is the DUB for H2AK13,15ub and regulates DNA damage response.

KEYWORDS:

DNA damage response; H2AK15ub; USP51; deubiqutylating enzyme

PMID:
27083998
PMCID:
PMC4840300
DOI:
10.1101/gad.271841.115
[Indexed for MEDLINE]
Free PMC Article

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