A chemical-genetic interaction map of the DNA damage response

Here we present data from 32 genome-scale loss-of-function CRISPRi chemical-genetic screens with inhibitors targeting core constituents of the DDR machinery (PARP, ATR, ATM, DNAPK, and WEE1), as both single agents and in combination with PARP inhibitors. These experiments identify >1000 genes whose perturbation modifies the DDR and provides a rich resource to the DDR community.

In addition, this compendium of functional genomics data reveals key principles governing the DDR and highlights a strong chemical-genetic interaction between loss of activity of the peroxiredoxin PRDX1 and all tested DDR inhibitors through a mechanism involving iron availability mediated by an MRGBP-PAX7-IREB2 axis. Our data position PRDX1 as a key suppressor of DNA damage accumulation and potential druggable target in combination with DDR inhibitors.