title: ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair.
abstract: Chromatin connects DNA damage response factors to sites of damaged DNA to promote the signaling and repair of DNA lesions. The histone H2A variants H2AX, H2AZ, and macroH2A represent key chromatin constituents that facilitate DNA repair. Through proteomic screening of these variants, we identified ZMYM3 (zinc finger, myeloproliferative, and mental retardation-type 3) as a chromatin-interacting protein that promotes DNA repair by homologous recombination (HR). ZMYM3 is recruited to DNA double-strand breaks through bivalent interactions with both histone and DNA components of the nucleosome. We show that ZMYM3 links the HR factor BRCA1 to damaged chromatin through specific interactions with components of the BRCA1-A subcomplex, including ABRA1 and RAP80. By regulating ABRA1 recruitment to damaged chromatin, ZMYM3 facilitates the fine-tuning of BRCA1 interactions with DNA damage sites and chromatin. Consistent with a role in regulating BRCA1 function, ZMYM3 deficiency results in impaired HR repair and genome instability. Thus, our work identifies a critical chromatin-binding DNA damage response factor, ZMYM3, which modulates BRCA1 functions within chromatin to ensure the maintenance of genome integrity.
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Justin W C
authors.initials: JW
authors.lastname: Leung
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.|The Howard Hughes Medical Institute, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Nodar
authors.initials: N
authors.lastname: Makharashvili
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Poonam
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Li-Ya
authors.initials: LY
authors.lastname: Chiu
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Renaud
authors.initials: R
authors.lastname: Pourpre
authors.affiliation: Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Cammarata
authors.affiliation: Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Joe R
authors.initials: JR
authors.lastname: Cannon
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G1X5, Canada.
authors.forename: Alana
authors.initials: A
authors.lastname: Sherker
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G1X5, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Durocher
authors.affiliation: Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Brodbelt
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.|The Howard Hughes Medical Institute, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Tanya T
authors.initials: TT
authors.lastname: Paull
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Miller
mesh_terms: D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins; D042822:Genomic Instability; D057809:HEK293 Cells; D056488:Histone Chaperones; D006657:Histones / Q000235:genetics / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
chemical_list: C520310:ABRAXAS1 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D056488:Histone Chaperones; D006657:Histones; D009687:Nuclear Proteins; C466234:UIMC1 protein, human; C102796:ZMYM3 protein, human
keywords: BRCA1-A complex; DNA damage response; DNA repair; ZMYM3; chromatin; homologous recombination