BRCA1, BRCA2, RAD51, and other DSB repair factors are regulated by CRL4/DDB1/WDR7

DNA double-strand break (DSB) repair pathway choice and fidelity are controlled by DNA damage response (DDR) factors including 53BP1 and BRCA1, which modulate 5 end resection. CRL4/DDB1/WDR70 is a conserved damage-responsive cullin ring ligase complexwith a proposed role in promoting 5 end resection. Using auxin-mediated degradation of WDR70, we show that WDR70 is an essential genome integrity factor that regulates multiple DSB repair pathways. WDR70 degradation elicits loss of BRCA1, BRCA2, RAD51 and other homology-dependent repair (HDR) proteins, 53BP1 and its downstream effectors RIF1/shieldin/CST/Pol/primase, and other DDR factors. In contrast, classical non -homologous end-joining (cNHEJ) factors were generally unchanged. Strikingly, WDR70 loss abrogated the localization of HDR factors, but not 53BP1/RIF1, to DNA damage foci. Mutation of the DDB1binding WD40 (DWD) motif, CRISPR disruption of DDB1, or inhibition of cullins resulted in a loss of WDR70 functions. Finally, RNA sequencing revealed that loss of WDR70 strongly affects the transcriptome, and particularly leads to reduced transcript levels of HDR factors. The data suggest that human WDR70 has a broad role in shaping the transcriptome and proteome, but also acts as a regulator of specific DSB repair pathways with a role in promoting the expression and localization of BRCA1/BRCA2/RAD