TY - JOUR
T1 - RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage
AU - Krais, John J.
AU - Wang, Yifan
AU - Patel, Pooja
AU - Basu, Jayati
AU - Bernhardy, Andrea J.
AU - Johnson, Neil
N1 - Funding Information:
This work was supported by US National Institutes of Health (NIH) Grants R01CA214799, R01HL150190, and R01GM135293. J.J.K. was supported by an American Cancer Society—Tri State CEOs Against Cancer Postdoctoral Fellowship, PF-19-097-01-DMC, Ovarian Cancer Research Alliance and Phil and Judy Messing grant 597484, and T32 CA009035. We are grateful to Sean Hua and the FCCC Transgenic Mouse facility for help generating mice as well as Genomics, Cell Culture and Cell Sorting facilities. We thank Dr. Ross Chapman for helpful discussions, Dr. Kathy Cai and the FCCC histopathology service for pathological analyses of mouse organs, and Dr. Beth Handorf for guidance with statistical analyses.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85113156615&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25346-4
DO - 10.1038/s41467-021-25346-4
M3 - Article
C2 - 34408138
AN - SCOPUS:85113156615
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5016
ER -