Comprehensive interrogation of synthetic lethality in the DNA damage response

Abstract The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability 1,2 . Unravelling the complementary interplay between these pathways remains a challenge 3,4 . Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind…