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

• Published in: Nature communications 2021-08, Vol.12 (1), p.5016-5016, Article 5016
• Main Authors: Krais, John J., Wang, Yifan, Patel, Pooja, Basu, Jayati, Bernhardy, Andrea J., Johnson, Neil
• Format: Article
• Language: English
• Subjects: 13/89; 14/1; 14/63; 631/67/68/2486; 631/80/641/151/1431; BRCA1 protein; BRCA2 protein; Breast cancer; Chromatin; Coils; Damage localization; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Domains; Epistasis; Histone H2A; Homologous recombination; Homologous recombination repair; Homology; Humanities and Social Sciences; Localization; Lysine; Molecular interactions; multidisciplinary; Mutation; Recruitment; Repair; Science; Science (multidisciplinary); Signal transduction; Signaling; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• 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 Brca1 CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168 − and Brca1 CC 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. The BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex is well known to play a fundamental role in DNA repair, but how the complex recruitment is regulated is still a matter of interest. Here the authors reveal mechanistic insights into RNF168 activity being responsible for PALB2 recruitment, through BARD1-BRCA1 during homologous recombination repair.