TDP1-independent pathways in the process and repair of TOP1-induced DNA damage

Here the authors find that MUS81 mediates excess DNA double strand break (DSB) generation in TDP1 KO cells after camptothecin treatment. They show that TOP1 cleavage complexes can be either resolved directly by TDP1 or be converted into DSBs and repaired further by the Homologous Recombination pathway. Anticancer drugs, such as camptothecin (CPT), trap topoisomerase I (TOP1) on DNA and form TOP1 cleavage complexes (TOP1cc). Alternative repair pathways have been suggested in the repair of TOP1cc. However, how these pathways work with TDP1, a key repair enzyme that specifically hydrolyze the covalent bond between TOP1 catalytic tyrosine and the 3'-end of DNA and contribute to the repair of TOP1cc is poorly understood. Here, using unbiased whole-genome CRISPR screens and generation of co-deficient cells with TDP1 and other genes, we demonstrate that MUS81 is an important factor that mediates the generation of excess double-strand breaks (DSBs) in TDP1 KO cells. APEX1/2 are synthetic lethal with TDP1. However, deficiency of APEX1/2 does not reduce DSB formation in TDP1 KO cells. Together, our data suggest that TOP1cc can be either resolved directly by TDP1 or be converted into DSBs and repaired further by the Homologous Recombination (HR) pathway.

Automated summary

The authors found that MUS81 plays a role in mediating excess DNA double-strand break (DSB) generation in TDP1 KO cells after camptothecin treatment. They demonstrate that TOP1 cleavage complexes can either be directly resolved by TDP1 or be converted into DSBs and repaired by the Homologous Recombination pathway.