TDP1-Independent Pathways in the Process and Repair of TOP1-Induced DNA Damage

Authors

Huimin Zhang
Yun Xiong
Dan Su
Chao Wang
Mrinal Srivastava
Mengfan Tang
Xu Feng
Min Huang
Zhen Chen
Junjie Chen

Publication Date

7-22-2022

Journal

Nature Communications

Abstract

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.

Keywords

Antineoplastic Agents, Camptothecin, DNA Damage, DNA Repair, DNA Topoisomerases, Type I, Phosphoric Diester Hydrolases, DNA damage response, Double-strand DNA breaks

DOI

10.1038/s41467-022-31801-7

PMID

35869071

PMCID

PMC9307636

PubMedCentral® Posted Date

7-22-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes