Mapping the genetic landscape of the DNA damage response with Cas12a-based combinatorial knockout screens - PubMed
3 hours ago
- #DNA Damage Response
- #Synthetic Lethality
- #CRISPR-Cas12a
- Unbiased genetic interaction screens using Cas12a genome editor to disrupt 233 DNA damage response (DDR) genes individually or in pairwise combinations.
- Assessment of phenotypic effects from >27,000 DDR gene pair combinations under unperturbed cell growth conditions, identifying over 750 high-confidence genetic interactions.
- Discovery of synthetic lethal interactions between specific gene pairs such as REV1-Pol complex and MCM8-MCM9-HROB, FA proteins and mitotic repair factors, and SMARCAL1 and FANCM complex components.
- Identification of suppressor interactions between APOLLO (DCLRE1B) and core NHEJ genes (XRCC4, LIG4, NHEJ1), suggesting NHEJ impairs fitness in APOLLO-deficient cells.
- Functional mapping of DDR network revealing novel pathways and therapeutic opportunities for cancers with mutations in identified genes.