BRCA1/BARD1 intrinsically disordered regions facilitate chromatin recruitment and ubiquitylation

Samuel R. Witus, Lisa M. Tuttle, Wenjing Li, Alex Zelter, Meiling Wang, Klaiten E. Kermoade, Damien B. Wilburn, Trisha N. Davis, Peter S. Brzovic, Weixing Zhao, Rachel E. Klevit

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

BRCA1/BARD1 is a tumor suppressor E3 ubiquitin (Ub) ligase with roles in DNA damage repair and in transcriptional regulation. BRCA1/BARD1 RING domains interact with nucleosomes to facilitate mono-ubiquitylation of distinct residues on the C-terminal tail of histone H2A. These enzymatic domains constitute a small fraction of the heterodimer, raising the possibility of functional chromatin interactions involving other regions such as the BARD1 C-terminal domains that bind nucleosomes containing the DNA damage signal H2A K15-Ub and H4 K20me0, or portions of the expansive intrinsically disordered regions found in both subunits. Herein, we reveal novel interactions that support robust H2A ubiquitylation activity mediated through a high-affinity, intrinsically disordered DNA-binding region of BARD1. These interactions support BRCA1/BARD1 recruitment to chromatin and sites of DNA damage in cells and contribute to their survival. We also reveal distinct BRCA1/BARD1 complexes that depend on the presence of H2A K15-Ub, including a complex where a single BARD1 subunit spans adjacent nucleosome units. Our findings identify an extensive network of multivalent BARD1-nucleosome interactions that serve as a platform for BRCA1/BARD1-associated functions on chromatin.

Original languageEnglish (US)
Article numbere113565
JournalEMBO Journal
Volume42
Issue number15
DOIs
StatePublished - Aug 1 2023

Keywords

  • BRCA1/BARD1
  • DNA repair
  • chromatin
  • intrinsically disordered region
  • ubiquitin

ASJC Scopus subject areas

  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology
  • Molecular Biology
  • General Neuroscience

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