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

Huimin Zhang, Yun Xiong, Dan Su, Chao Wang, Mrinal Srivastava, Mengfan Tang, Xu Feng, Min Huang, Zhen Chen and Junjie Chen ()
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Huimin Zhang: The University of Texas MD Anderson Cancer Center
Yun Xiong: The University of Texas MD Anderson Cancer Center
Dan Su: The University of Texas MD Anderson Cancer Center
Chao Wang: The University of Texas MD Anderson Cancer Center
Mrinal Srivastava: The University of Texas MD Anderson Cancer Center
Mengfan Tang: The University of Texas MD Anderson Cancer Center
Xu Feng: The University of Texas MD Anderson Cancer Center
Min Huang: The University of Texas MD Anderson Cancer Center
Zhen Chen: The University of Texas MD Anderson Cancer Center
Junjie Chen: The University of Texas MD Anderson Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31801-7

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