Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin
Abstract Background Bleomycin (Bleo) is a glycopeptide with potent antitumor activity that induces DNA double-strand breaks (DSBs) through free radical generation, similar to ionizing radiation (IR). Therefore, Bleo is considered a radiomimetic drug. However, differences in DNA repair mechanisms bet...
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BMC
2025-03-01
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| Series: | Genes and Environment |
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| Online Access: | https://doi.org/10.1186/s41021-025-00329-9 |
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| author | Naoto Shimizu Kazuki Izawa Mubasshir Washif Ryosuke Morozumi Kouji Hirota Masataka Tsuda |
| author_facet | Naoto Shimizu Kazuki Izawa Mubasshir Washif Ryosuke Morozumi Kouji Hirota Masataka Tsuda |
| author_sort | Naoto Shimizu |
| collection | DOAJ |
| description | Abstract Background Bleomycin (Bleo) is a glycopeptide with potent antitumor activity that induces DNA double-strand breaks (DSBs) through free radical generation, similar to ionizing radiation (IR). Therefore, Bleo is considered a radiomimetic drug. However, differences in DNA repair mechanisms between IR- and Bleo-induced DNA damage have not been fully elucidated. Therefore, in the present study, we examined a panel of repair-deficient human TK6 cell lines to elucidate the relative contributions of individual repair factors. Results Our comprehensive profiling indicated that both non-homologous end joining (NHEJ) and homologous recombination (HR) contributed to DSB repair induced by X-rays and Bleo. Furthermore, tyrosyl-DNA phosphodiesterase (TDP)-related repair was a significant factor for cellular sensitivity to Bleo treatment. TDP1 −/− /TDP2 −/− cells exhibited greater sensitivity to Bleo than TDP1 −/− or TDP2 −/− cells, but not to X-rays. In addition, we determined whether TDP2 is involved in the repair of Bleo-induced DSBs using a neutral comet assay. In TDP1-deficient cells, knockout of TDP2 resulted in a significant delay in the repair kinetics of DSBs induced by Bleo, but not by X-rays. Conclusions The contribution of the TDP-related pathway to DSB repair significantly differed between IR and radiomimetic drugs. The discovery of this novel TDP2-dependent repair of DSBs resulting from radiomimetic drug exposure indicates that TDP1 and TDP2 inhibition in combination with radiomimetic drugs represents a strategy for cancer treatment. |
| format | Article |
| id | doaj-art-8e6b8aff2dda4e988b1db19d7b45991a |
| institution | Kabale University |
| issn | 1880-7062 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Genes and Environment |
| spelling | doaj-art-8e6b8aff2dda4e988b1db19d7b45991a2025-08-20T03:40:48ZengBMCGenes and Environment1880-70622025-03-0147111010.1186/s41021-025-00329-9Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug BleomycinNaoto Shimizu0Kazuki Izawa1Mubasshir Washif2Ryosuke Morozumi3Kouji Hirota4Masataka Tsuda5Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima UniversityDivision of Genome Safety Science, National Institute of Health SciencesDepartment of Chemistry, Graduate School of Science, Tokyo Metropolitan UniversityProgram of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima UniversityDepartment of Chemistry, Graduate School of Science, Tokyo Metropolitan UniversityProgram of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima UniversityAbstract Background Bleomycin (Bleo) is a glycopeptide with potent antitumor activity that induces DNA double-strand breaks (DSBs) through free radical generation, similar to ionizing radiation (IR). Therefore, Bleo is considered a radiomimetic drug. However, differences in DNA repair mechanisms between IR- and Bleo-induced DNA damage have not been fully elucidated. Therefore, in the present study, we examined a panel of repair-deficient human TK6 cell lines to elucidate the relative contributions of individual repair factors. Results Our comprehensive profiling indicated that both non-homologous end joining (NHEJ) and homologous recombination (HR) contributed to DSB repair induced by X-rays and Bleo. Furthermore, tyrosyl-DNA phosphodiesterase (TDP)-related repair was a significant factor for cellular sensitivity to Bleo treatment. TDP1 −/− /TDP2 −/− cells exhibited greater sensitivity to Bleo than TDP1 −/− or TDP2 −/− cells, but not to X-rays. In addition, we determined whether TDP2 is involved in the repair of Bleo-induced DSBs using a neutral comet assay. In TDP1-deficient cells, knockout of TDP2 resulted in a significant delay in the repair kinetics of DSBs induced by Bleo, but not by X-rays. Conclusions The contribution of the TDP-related pathway to DSB repair significantly differed between IR and radiomimetic drugs. The discovery of this novel TDP2-dependent repair of DSBs resulting from radiomimetic drug exposure indicates that TDP1 and TDP2 inhibition in combination with radiomimetic drugs represents a strategy for cancer treatment.https://doi.org/10.1186/s41021-025-00329-9Radiomimetic drugsBleomycinIonizing radiationDNA double-strand breaksTK6Tyrosyl-DNA phosphodiesterase |
| spellingShingle | Naoto Shimizu Kazuki Izawa Mubasshir Washif Ryosuke Morozumi Kouji Hirota Masataka Tsuda Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin Genes and Environment Radiomimetic drugs Bleomycin Ionizing radiation DNA double-strand breaks TK6 Tyrosyl-DNA phosphodiesterase |
| title | Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin |
| title_full | Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin |
| title_fullStr | Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin |
| title_full_unstemmed | Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin |
| title_short | Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin |
| title_sort | role of tdp2 in the repair of dna damage induced by the radiomimetic drug bleomycin |
| topic | Radiomimetic drugs Bleomycin Ionizing radiation DNA double-strand breaks TK6 Tyrosyl-DNA phosphodiesterase |
| url | https://doi.org/10.1186/s41021-025-00329-9 |
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