title: NuMA promotes homologous recombination repair by regulating the accumulation of the ISWI ATPase SNF2h at DNA breaks.
abstract: Chromatin remodeling factors play an active role in the DNA damage response by shaping chromatin to facilitate the repair process. The spatiotemporal regulation of these factors is key to their function, yet poorly understood. We report that the structural nuclear protein NuMA accumulates at sites of DNA damage in a poly[ADP-ribose]ylation-dependent manner and functionally interacts with the ISWI ATPase SNF2h/SMARCA5, a chromatin remodeler that facilitates DNA repair. NuMA coimmunoprecipitates with SNF2h, regulates its diffusion in the nucleoplasm and controls its accumulation at DNA breaks. Consistent with NuMA enabling SNF2h function, cells with silenced NuMA exhibit reduced chromatin decompaction after DNA cleavage, lesser focal recruitment of homologous recombination repair factors, impaired DNA double-strand break repair in chromosomal (but not in episomal) contexts and increased sensitivity to DNA cross-linking agents. These findings reveal a structural basis for the orchestration of chromatin remodeling whereby a scaffold protein promotes genome maintenance by directing a remodeler to DNA breaks.
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, USA lelievre@purdue.edu.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Vidi
authors.affiliation: Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Salles
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Swaathi
authors.initials: S
authors.lastname: Jayaraman
authors.affiliation: Department of Biomedical Engineering, and Chemical & Biochemical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: George
authors.initials: G
authors.lastname: Dorfman
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gray
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Abad
authors.affiliation: Department of Biomedical Engineering, and Chemical & Biochemical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Prabhas V
authors.initials: PV
authors.lastname: Moghe
authors.affiliation: Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Irudayaraj
authors.affiliation: Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, USA Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA lelievre@purdue.edu.
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Lelièvre
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D034961:Antigens, Nuclear / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D006657:Histones / Q000378:metabolism; D006801:Humans; D034521:Nuclear Matrix-Associated Proteins / Q000502:physiology*; D059767:Recombinational DNA Repair
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D000251:Adenosine Triphosphatases; C409462:SMARCA5 protein, human
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