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Structural insight into BRCA1-BARD1 complex recruitment to damaged chromatin
Linchang Dai1, Yaxin Dai1, Jinhua Han2
1National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Molecular Cell
|June 8, 2021
Summary
The BRCA1-BARD1 complex recruits to DNA damage sites via BARD1
Area of Science:
- Molecular Biology
- Structural Biology
- Genetics
Background:
- The BRCA1-BARD1 complex is crucial for DNA double-strand break (DSB) repair via homologous recombination (HR).
- Recruitment of BRCA1-BARD1 to DSB sites depends on BARD1's interaction with nucleosomes and specific histone marks.
Purpose of the Study:
- To elucidate the structural mechanism of BARD1's interaction with ubiquitinated nucleosomes.
- To understand how BARD1 recognizes histone marks and facilitates BRCA1-BARD1 complex targeting to DSBs.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine the structure of BARD1 bound to a ubiquitinated nucleosome core particle (NCPUb).
- In vitro and in vivo biochemical and cellular assays to analyze the functional significance of BARD1-nucleosome interactions.
Main Results:
- Determined the 3.1 Å cryo-EM structure of BARD1 on NCPUb, revealing simultaneous recognition of H2AK15ub and H4K20me0 marks.
- Demonstrated that BARD1-nucleosome, BARD1-ubiquitin, and intramolecular BARD1 domain interactions stabilize the complex.
- Showed that disrupting these interactions impairs homologous recombination (HR) activity.
- Identified disease-causing BARD1 mutations that disrupt these interactions and impair HR.
Conclusions:
- Elucidated the mechanism of BRCA1-BARD1 recruitment and retention at DSB-flanking nucleosomes.
- Highlighted the critical role of BARD1's interaction with modified nucleosomes in DNA repair.
- Provided insights into potential cancer therapeutic strategies targeting DNA repair pathways.
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