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Tyrosyl DNA\u2010phosphodiesterase 1 (TDP1) hydrolyzes the phosphodiester bond between DNA 3\u2032\u2010end and a tyrosyl moiety of trapped topoisomerase I\u2010DNA covalent complexes (Top1cc). We have previously shown\n                    <jats:italic>Leishmania<\/jats:italic>\n                    harbors a TDP1\u00a0gene (LdTDP1), however, the biological role of TDP1\u00a0remains largely unknown. In the present study, we have generated TDP1\u00a0knockout\n                    <jats:italic>L. donovani<\/jats:italic>\n                    (LdTDP1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) promastigotes and have shown that LdTDP1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    parasites are deficient in 3\u2032\u2010phosphodiesterase activities and were hypersensitive to Top1\u2010poison like camptothecin (CPT), DNA alkylation agent like methyl methanesulfonate, and oxidative DNA lesions generated by hydrogen peroxide but were not sensitive to etoposide. We also detected elevated levels of CPT\u2010induced reactive oxygen species triggering cell cycle arrest and cell death in LdTDP1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    promastigotes. LdTDP1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    promastigotes accumulate a significant change in the membrane morphology with the accumulation of membrane pores, which is associated with oxidative stress and lipid peroxidation. To our surprise, we detected that LdTDP1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    parasites were hypersensitive to antileishmanial drugs like amphotericin B and miltefosine, which could be rescued by complementation of wild\u2010type TDP1\u00a0gene in the LdTDP1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    parasites. Notably, multidrug\u2010resistant\n                    <jats:italic>L. donovani<\/jats:italic>\n                    \u00a0clinical isolates showed a marked reduction in TDP1 expression and were sensitive to Top1 poisons. Taken together, our study provides a new role of LdTDP1 in protecting\u00a0\n                    <jats:italic>L. donovani<\/jats:italic>\n                    \u00a0parasites from oxidative stress\u2010induced DNA damage and resistance to amphotericin B and miltefosine.\n                  <\/jats:p>","DOI":"10.1096\/fj.202101668rr","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T10:45:42Z","timestamp":1648032342000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["TDP1 knockout\n                    <i>Leishmania donovani<\/i>\n                    accumulate topoisomerase 1\u2010linked DNA damage and are hypersensitive to clinically used antileishmanial drugs"],"prefix":"10.1096","volume":"36","author":[{"given":"Somenath Roy","family":"Chowdhury","sequence":"first","affiliation":[{"name":"Infectious Diseases &amp; Immunology Division CSIR\u2010Indian Institute of Chemical 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