In this study, we used Cas12a to disrupt >27,000 combinations of 233 DNA damage response genes in MCF10A and RPE-1 p53 KO cells, monitoring changes in cell viability. From this analysis, we identified over 750 high-confidence positive (buffering) or negative (synthetic lethal/sick) interactions.
This work wouldn't have been possible without @angelotaglialatela.bsky.social, Jen-Wei Huang, @giuseppeleuzzi.bsky.social, and members of the labs of @traver.bsky.social, Raphael Guerois, @labvincenzo.bsky.social, Raul Rabadan, @nussenza.bsky.social, @jenscs83.bsky.social, @heyzajr.bsky.social.
We uncovered synthetic lethal interactions between Fanconi anemia genes and GEN1, CIP2A, and RHNO1; the translesion polymerase REV1-Pol ζ and the MCM8/9-HROB DNA helicase; and the DNA translocase SMARCAL1 and the FANCM complex, as reported also by @durocher1.bsky.social and @jcornlab.bsky.social.
Our full dataset can be queried at ddr-genetic-interactions.ciccialab-database.com
This has been an 8-year journey, and we hope that our studies will be useful to the community!
Additionally, we identified robust suppressor interactions between the DCLRE1B gene encoding the nuclease APOLLO and the NHEJ genes XRCC4, LIG4, and NHEJ1.