RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage

Yifan Wang, Pooja Patel, Jayati Basu, Andrea J. Bernhardy, Neil Johnson, John J. Krais

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

DNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168 and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.

Original languageEnglish
Article number5016
Pages (from-to)5016
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - Jul 18 2021

Keywords

  • Animals
  • BRCA1 Protein/genetics
  • Cell Nucleus/genetics
  • DNA Damage
  • DNA/genetics
  • Fanconi Anemia Complementation Group N Protein/genetics
  • Histones/genetics
  • Humans
  • Mice
  • Protein Binding
  • Protein Transport
  • Rad51 Recombinase/genetics
  • Recombinational DNA Repair
  • Tumor Suppressor Proteins/genetics
  • Ubiquitin-Protein Ligases/genetics
  • Ubiquitination

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