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

Nat Commun. 2021 Aug 18;12(1):5016. doi: 10.1038/s41467-021-25346-4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • BRCA1 Protein
  • BRCA1 protein, human
  • Fanconi Anemia Complementation Group N Protein
  • Histones
  • PALB2 protein, human
  • Tumor Suppressor Proteins
  • DNA
  • BARD1 protein, human
  • RNF168 protein, human
  • Ubiquitin-Protein Ligases
  • Rad51 Recombinase