BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination

Nature. 2021 Aug;596(7872):433-437. doi: 10.1038/s41586-021-03776-w. Epub 2021 Jul 28.


Protein ubiquitination at sites of DNA double-strand breaks (DSBs) by RNF168 recruits BRCA1 and 53BP11,2, which are mediators of the homologous recombination and non-homologous end joining DSB repair pathways, respectively3. Non-homologous end joining relies on 53BP1 binding directly to ubiquitinated lysine 15 on H2A-type histones (H2AK15ub)4,5 (which is an RNF168-dependent modification6), but how RNF168 promotes BRCA1 recruitment and function remains unclear. Here we identify a tandem BRCT-domain-associated ubiquitin-dependent recruitment motif (BUDR) in BRCA1-associated RING domain protein 1 (BARD1) (the obligate partner protein of BRCA1) that, by engaging H2AK15ub, recruits BRCA1 to DSBs. Disruption of the BUDR of BARD1 compromises homologous recombination and renders cells hypersensitive to PARP inhibition and cisplatin. We further show that BARD1 binds nucleosomes through multivalent interactions: coordinated binding of H2AK15ub and unmethylated H4 lysine 20 by its adjacent BUDR and ankyrin repeat domains, respectively, provides high-affinity recognition of DNA lesions in replicated chromatin and promotes the homologous recombination activities of the BRCA1-BARD1 complex. Finally, our genetic epistasis experiments confirm that the need for BARD1 chromatin-binding activities can be entirely relieved upon deletion of RNF168 or 53BP1. Thus, our results demonstrate that by sensing DNA-damage-dependent and post-replication histone post-translation modification states, BRCA1-BARD1 complexes coordinate the antagonization of the 53BP1 pathway with promotion of homologous recombination, establishing a simple paradigm for the governance of the choice of DSB repair pathway.

Publication types

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

MeSH terms

  • Adult
  • Amino Acid Motifs
  • BRCA1 Protein / chemistry
  • BRCA1 Protein / metabolism
  • Chromatin / metabolism
  • Cisplatin / pharmacology
  • DNA Breaks, Double-Stranded
  • DNA Damage / drug effects
  • Female
  • HCT116 Cells
  • HEK293 Cells
  • Histones / chemistry
  • Histones / metabolism
  • Homologous Recombination*
  • Humans
  • Lysine / chemistry*
  • Lysine / metabolism*
  • Male
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Protein Domains
  • Recombinational DNA Repair
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism*
  • Tumor Suppressor p53-Binding Protein 1 / deficiency
  • Tumor Suppressor p53-Binding Protein 1 / metabolism
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*


  • BRCA1 Protein
  • Chromatin
  • Histones
  • Poly(ADP-ribose) Polymerase Inhibitors
  • TP53BP1 protein, human
  • Tumor Suppressor Proteins
  • Tumor Suppressor p53-Binding Protein 1
  • Ubiquitin
  • BARD1 protein, human
  • RNF168 protein, human
  • Ubiquitin-Protein Ligases
  • Lysine
  • Cisplatin