title: USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA;
authors.forename: Zhiquan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA;
authors.forename: Honglian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA;
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Abigael
authors.initials: A
authors.lastname: Cheruiyot
authors.affiliation: 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;
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA;
authors.forename: Tamas
authors.initials: T
authors.lastname: Ordog
authors.affiliation: Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: You
authors.affiliation: 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;
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004247:DNA / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011839:Radiation, Ionizing; D015534:Trans-Activators / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D006657:Histones; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D004247:DNA; C579193:USP51 protein, human; D064570:Ubiquitin-Specific Proteases
keywords: DNA damage response; H2AK15ub; USP51; deubiqutylating enzyme