Two redundant ubiquitin-dependent pathways of BRCA1 localization to DNA damage sites

ABSTRACT: The tumor suppressor BRCA1 accumulates at sites of DNA damage in a ubiquitin-dependent manner. In this work, we revisit the role of RAP80 in promoting BRCA1 recruitment to damaged chromatin. We find that RAP80 acts redundantly with the BRCA1 RING domain to promote BRCA1 recruitment to DNA damage sites. We show that that RNF8 E3 ligase acts upstream of both the RAP80- and RING-dependent activities whereas RNF168 acts uniquely upstream of the RING domain. BRCA1 RING mutations that do not impact BARD1 interaction, such as the E2-binding deficient I26A mutation, renders BRCA1 unable to accumulate at DNA damage sites in the absence of RAP80. Cells that combine BRCA1 I26A and mutations that disable the RAP80-BRCA1 interaction are hypersensitive to PARP inhibition and are unable to form RAD51 foc

SUBMITTER: Mrs. Alana Sherker 

PROVIDER: S-SCDT-EMBOR-2021-53679V1 | biostudies-other |

REPOSITORIES: biostudies-other