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Published on: June 26, 2020
ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair
Justin W C Leung1, Nodar Makharashvili1,2, Poonam Agarwal1
1Department 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.
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.
Insights
Researchers discovered ZMYM3, a protein that binds chromatin and aids DNA repair. ZMYM3 connects BRCA1 to DNA damage sites, ensuring genome stability by facilitating homologous recombination (HR) repair.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Chromatin plays a crucial role in DNA damage response (DDR) by recruiting repair factors.
- Histone H2A variants (H2AX, H2AZ, macroH2A) are key chromatin components involved in DNA repair.
- Understanding novel chromatin-interacting proteins in DDR is essential for comprehending genome maintenance.
Purpose of the Study:
- To identify novel chromatin-interacting proteins involved in DNA repair.
- To elucidate the role of ZMYM3 in DNA double-strand break repair, particularly homologous recombination (HR).
- To investigate the mechanism by which ZMYM3 modulates BRCA1 function at DNA damage sites.
Main Methods:
- Proteomic screening of histone H2A variants.
- Biochemical assays to study protein-protein interactions.
- Cellular assays to assess DNA repair efficiency and genome instability.
Main Results:
- ZMYM3 was identified as a chromatin-interacting protein that promotes homologous recombination (HR) repair.
- ZMYM3 is recruited to DNA double-strand breaks via interactions with both histone and DNA components of nucleosomes.
- ZMYM3 bridges BRCA1 to damaged chromatin by interacting with the BRCA1-A subcomplex (ABRA1, RAP80), fine-tuning BRCA1 recruitment.
Conclusions:
- ZMYM3 is a novel chromatin-binding factor critical for DNA damage response.
- ZMYM3 facilitates HR repair by modulating BRCA1 function at DNA damage sites.
- ZMYM3 deficiency leads to impaired HR repair and genome instability, highlighting its importance in maintaining genome integrity.
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