ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair

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 Z...

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Bibliographic Details
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
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.292516.116