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.
Highlights
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
By using a modified version of the procedure described by O’Callaghan et al.[27], we measured by quantitative PCR (qPCR) oxidative DNA damage at telomeric DNA or the 36B4 locus, whose amplified regions contain a similar percentage of G:C base pairs (50% telomeres vs 52% 36B4)
We have confirmed that TH5487 blocks BER initiation at telomeres in response to oxidative stress (OS), and we have characterized some of the TH5487 related telomeric and non-telomeric phenotypes in U2OS cells
Summary
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. Dysfunctional telomeres, arising from the loss of telomeric repeats and/or sheltering protection, are recognized by many DNA damage response proteins, including the phosphorylated H2A histone family member X at serine 139 (γH2AX) or the p53-binding protein 1 (53BP1), that form telomere dysfunction-induced foci (TIF) and lead to genomic instability, cell proliferation defects or apoptosis[4,5]. 8-oxoG decreases the binding of the shelterin c omplex[13,14], potentially leading to telomere shortening, uncapping and telomere crisis[14,15,16] This is a cellular state characterized by extensive genomic instability, including translocations, amplifications, and deletions related to aging-induced processes and cancer[17]
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