Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates Methotrexate anticancer effects

Abstract

Background: The most common oxidative DNA lesion is 8-oxoguanine (8-oxoG) which is mainly recognized and excised by the glycosylase OGG1, initiating the Base Excision Repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress which disrupts telomere homeostasis triggering genome instability. Methods: We used U2OS OGG1-GFP osteosarcoma cell line to study the role of OGG1 at the telomeres in response to oxidative stress. Next, we investigated the effects of inactivating pharmacologically the BER during oxidative stress (OS) conditions by using a specific small molecule inhibitor of OGG1 (TH5487) in different human cell lines. Results: We have found that during OS, TH5487 effectively blocks BER initiation at telomeres causing accumulation of oxidized bases at this region, correlating with other phenotypes such as telomere losses, micronuclei formation and mild proliferation defects. Besides, the antimetabolite Methotrexate synergizes with TH5487 through induction of intracellular ROS formation, which potentiates TH5487 mediated telomere and genome instability in different cell lines. Conclusions: 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.

Telomeric 8-Oxoguanine Drives Rapid Premature Senescence In The Absence Of Telomere Shortening

“…The accumulation of telomeric 8oxoG in cells lacking OGG1 enzyme which removes 8oxoG, increases hallmarks of telomere crisis including chromosomes fusions and chromatid bridges. This study, and work from others, provide evidence that accumulation of unrepaired 8oxoG can drive telomere instability in human cancer cells (Baquero et al, 2021;Fouquerel et al, 2019). However, a potential role for telomeric 8oxoG in cellular senescence and aging could not be delineated in genetically unstable cancer cell lines.…”