The deubiquitinating enzyme Cezanne stabilizes BRCA1 by counteracting APC/C and Ube2S-dependent Lys11-linked ubiquitination

The breast and ovarian tumor suppressor BRCA1 is a cell cycle-regulated protein and tumors with reduced BRCA1 protein level may share molecular features of BRCA1-mutant tumor and respond to PARPi therapy. Here, we identify that BRCA1 protein stability is controlled through ubiquitin lysine 11 (K11)-linkage modification under the regulation of Cezanne deubiquitinating enzyme, APC/C E3 ligase, and Ube2S E2 conjugating enzyme in a cell cycle-dependent manner. Cezanne-deficiency leads to increased BRCA1 K11-ubiquitination, decreased BRCA1 protein level, and increased cellular sensitivity to PARPi. The BRCA1 K11-linked ubiquitination is carried out through a degron on BRCA1 that is recognized by APC/C cofactor Cdh1. Tumor expression and mutational analyses indicate that Cezanne low or Ube2S high expression is associated with "BRCAness" and correlated with poor prognosis in breast cancer patients. Thus, our study has demonstrated a ubiquitin K11-linked ubiquitination pathway that regulates BRCA1 protein stability, dysregulation of which predicts BRCA1-deficiency that may be effectively targeted with PARPi therapy.