Antoine Simoneau, Justin L Engel, Madhavi Bandi, Katherine Lazarides, Shangtao Liu, Samuel R Meier, Ashley H Choi, Hongxiang Zhang, Binzhang Shen, Lauren Martires, Deepali Gotur, Truc V Pham, Fang Li, Lina Gu, Shanzhong Gong, Minjie Zhang, Erik Wilker, Xuewen Pan, Douglas A Whittington, Scott Throner, John P Maxwell, Yingnan Chen, Yi Yu, Alan Huang, Jannik N Andersen, Tianshu Feng
CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacologic inhibition of USP1 leads to decreased DNA synthesis concomitant with S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identify RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as mediators of USP1 dependency...
February 1, 2023: Molecular Cancer Therapeutics