ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair

• Published in: Genes & development 2017-02, Vol.31 (3), p.260-274
• Main Authors: Leung, Justin W C, Makharashvili, Nodar, Agarwal, Poonam, Chiu, Li-Ya, Pourpre, Renaud, Cammarata, Michael B, Cannon, Joe R, Sherker, Alana, Durocher, Daniel, Brodbelt, Jennifer S, Paull, Tanya T, Miller, Kyle M
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Chromatin - genetics; Chromatin - metabolism; DNA Breaks, Double-Stranded; DNA Repair; DNA-Binding Proteins; Genomic Instability; HEK293 Cells; Histone Chaperones; Histones - genetics; Histones - metabolism; Homologous Recombination; Humans; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Osteosarcoma - genetics; Osteosarcoma - metabolism; Research Paper; Sequence Homology, Amino Acid; Tumor Cells, Cultured
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.292516.116

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.