RT Journal Article
SR Electronic
T1 RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.25.449923
DO 10.1101/2021.06.25.449923
A1 John J. Krais
A1 Yifan Wang
A1 Pooja Patel
A1 Jayati Basu
A1 Andrea J. Bernhardy
A1 Neil Johnson
YR 2021
UL http://biorxiv.org/content/early/2021/06/25/2021.06.25.449923.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.