7E8I

Structural insight into BRCA1-BARD1 complex recruitment to damaged chromatin

Summary for 7E8I

• Entry DOI: 10.2210/pdb7e8i/pdb
• EMDB information: 31020
• Descriptor: DNA (145-MER), Histone H3, Histone H4, ... (8 entities in total)
• Functional Keywords: brca1, nucleosome, dna damage, chromatin, bard1, nuclear protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 12
• Total formula weight: 247503.23

Authors

Dai, Y.,Dai, L.,Zhou, Z. (deposition date: 2021-03-01, release date: 2021-06-30, Last modification date: 2024-03-27)

Primary citation

Dai, L.,Dai, Y.,Han, J.,Huang, Y.,Wang, L.,Huang, J.,Zhou, Z.
Structural insight into BRCA1-BARD1 complex recruitment to damaged chromatin.
Mol.Cell, 81:2765-2777.e6, 2021

PubMed Abstract: The BRCA1-BARD1 complex directs the DNA double-strand break (DSB) repair pathway choice to error-free homologous recombination (HR) during the S-G2 stages. Targeting BRCA1-BARD1 to DSB-proximal sites requires BARD1-mediated nucleosome interaction and histone mark recognition. Here, we report the cryo-EM structure of BARD1 bound to a ubiquitinated nucleosome core particle (NCP) at 3.1 Å resolution and illustrate how BARD1 simultaneously recognizes the DNA damage-induced mark H2AK15ub and DNA replication-associated mark H4K20me0 on the nucleosome. In vitro and in vivo analyses reveal that the BARD1-NCP complex is stabilized by BARD1-nucleosome interaction, BARD1-ubiquitin interaction, and BARD1 ARD domain-BARD1 BRCT domain interaction, and abrogating these interactions is detrimental to HR activity. We further identify multiple disease-causing BARD1 mutations that disrupt BARD1-NCP interactions and hence impair HR. Together, this study elucidates the mechanism of BRCA1-BARD1 complex recruitment and retention by DSB-flanking nucleosomes and sheds important light on cancer therapeutic avenues.

PubMed: 34102105
DOI: 10.1016/j.molcel.2021.05.010

Experimental method

ELECTRON MICROSCOPY (3.1 Å)