TDP1 deficiency sensitizes human cells to base damage via distinct topoisomerase I and PARP mechanisms with potential applications for cancer therapy

Nucleic Acids Research
M AlagozSherif F El-Khamisy

Abstract

Base damage and topoisomerase I (Top1)-linked DNA breaks are abundant forms of endogenous DNA breakage, contributing to hereditary ataxia and underlying the cytotoxicity of a wide range of anti-cancer agents. Despite their frequency, the overlapping mechanisms that repair these forms of DNA breakage are largely unknown. Here, we report that depletion of Tyrosyl DNA phosphodiesterase 1 (TDP1) sensitizes human cells to alkylation damage and the additional depletion of apurinic/apyrimidinic endonuclease I (APE1) confers hypersensitivity above that observed for TDP1 or APE1 depletion alone. Quantification of DNA breaks and clonogenic survival assays confirm a role for TDP1 in response to base damage, independently of APE1. The hypersensitivity to alkylation damage is partly restored by depletion of Top1, illustrating that alkylating agents can trigger cytotoxic Top1-breaks. Although inhibition of PARP activity does not sensitize TDP1-deficient cells to Top1 poisons, it confers increased sensitivity to alkylation damage, highlighting partially overlapping roles for PARP and TDP1 in response to genotoxic challenge. Finally, we demonstrate that cancer cells in which TDP1 is inherently deficient are hypersensitive to alkylation damage ...Continue Reading

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Citations

Feb 5, 2014·Nucleic Acids Research·Benu Brata DasYves Pommier
Oct 22, 2014·Proceedings of the National Academy of Sciences of the United States of America·DongYu GuoHoward A Nash
Mar 1, 2015·FEMS Microbiology Reviews·Andrea Sánchez-ValletBart P H J Thomma
May 27, 2014·DNA Repair·Yves PommierChristophe Marchand
Dec 8, 2017·Nucleic Acids Research·Ajinkya S Kawale, Lawrence F Povirk
May 8, 2020·Organic & Biomolecular Chemistry·Long-Gao XiaoLin-Kun An
Sep 6, 2019·International Journal of Molecular Sciences·Janina EnderleHolger Puchta
Feb 20, 2015·Nature Reviews. Cancer·Mohamed E AshourSherif F El-Khamisy
Aug 31, 2017·Scientific Reports·Thomas StröbelNurten Saydam
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Feb 10, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Chao MeiZhao-Qian Liu
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Elizaveta D GladkovaNariman F Salakhutdinov
Jul 25, 2021·Sensors·Ann-Katrine JakobsenMagnus Stougaard
Dec 10, 2016·Journal of Natural Products·Alexandra ZakharenkoOlga Lavrik

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Methods Mentioned

BETA
transfection
electrophoresis
Assay
gene knockout

Software Mentioned

Comet Assay IV
Corel Photo Draw
SigmaPlot

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