The nuclease EXO1 promotes genomic instability by degrading nascent DNA in BRCA-proficient cells

DNA repair genes are generally considered tumor suppressors, as their inactivation is observed in tumors and is associated with carcinogenesis. Mutations in BRCA1 and BRCA2 genes are observed in breast, ovarian, and other cancers. This results in defective homologous recombination DNA repair, as well as in degradation of nascent DNA during replication stress, catalyzed by exonucleases including EXO1 and MRE11. However, most tumors are BRCA pathway-proficient. Here, we show that EXO1 is overexpressed in a significant proportion of tumors. EXO1 overexpression causes the degradation of nascent DNA at both single stranded DNA (ssDNA) gaps and reversed replication forks. Importantly, this degradation occurs efficiently in BRCA-proficient cells, through cooperation with MRE11. This results in increased double strand break formation and hypersensitivity to genotoxic agents. We thus identify increased EXO1 activity as a mechanism of genomic instability similar to BRCA pathway inactivation, but occurring more frequently in tumors compared to BRCA inactivation.