Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects
Abstract The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering...
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2021
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oai:doaj.org-article:1b489d3921bb4809ad1aa6047fd0bc202021-12-02T12:14:50ZSmall molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects10.1038/s41598-021-82917-72045-2322https://doaj.org/article/1b489d3921bb4809ad1aa6047fd0bc202021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82917-7https://doaj.org/toc/2045-2322Abstract The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.Juan Miguel BaqueroCarlos Benítez-BuelgaVarshni RajagopalZhao ZhenjunRaúl Torres-RuizSarah MüllerBishoy M. F. HannaOlga LosevaOlov WallnerMaurice MichelSandra Rodríguez-PeralesHelge GadTorkild VisnesThomas HelledayJavier BenítezAna OsorioNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) |
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Medicine R Science Q Juan Miguel Baquero Carlos Benítez-Buelga Varshni Rajagopal Zhao Zhenjun Raúl Torres-Ruiz Sarah Müller Bishoy M. F. Hanna Olga Loseva Olov Wallner Maurice Michel Sandra Rodríguez-Perales Helge Gad Torkild Visnes Thomas Helleday Javier Benítez Ana Osorio Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects |
| description |
Abstract The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment. |
| format |
article |
| author |
Juan Miguel Baquero Carlos Benítez-Buelga Varshni Rajagopal Zhao Zhenjun Raúl Torres-Ruiz Sarah Müller Bishoy M. F. Hanna Olga Loseva Olov Wallner Maurice Michel Sandra Rodríguez-Perales Helge Gad Torkild Visnes Thomas Helleday Javier Benítez Ana Osorio |
| author_facet |
Juan Miguel Baquero Carlos Benítez-Buelga Varshni Rajagopal Zhao Zhenjun Raúl Torres-Ruiz Sarah Müller Bishoy M. F. Hanna Olga Loseva Olov Wallner Maurice Michel Sandra Rodríguez-Perales Helge Gad Torkild Visnes Thomas Helleday Javier Benítez Ana Osorio |
| author_sort |
Juan Miguel Baquero |
| title |
Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects |
| title_short |
Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects |
| title_full |
Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects |
| title_fullStr |
Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects |
| title_full_unstemmed |
Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects |
| title_sort |
small molecule inhibitor of ogg1 blocks oxidative dna damage repair at telomeres and potentiates methotrexate anticancer effects |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/1b489d3921bb4809ad1aa6047fd0bc20 |
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