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

Affiliation

Baquero JM(#)(1), Benítez-Buelga C(#)(2), Rajagopal V(3), Zhenjun Z(3), Torres-Ruiz R(4)(5), Müller S(3), Hanna BMF(3), Loseva O(3), Wallner O(3), Michel M(3), Rodríguez-Perales S(4), Gad H(6), Visnes T(7), Helleday T(3)(6), Benítez J(1)(8)(9), Osorio A(10)(11).
Author information:
(1)Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre
(CNIO), 28029, Madrid, Spain.
(2)Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 17121, Solna, Sweden. [Email]
(3)Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 17121, Solna, Sweden.
(4)Molecular Cytogenetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre
(CNIO), 28029, Madrid, Spain.
(5)Department of Biomedicine, School of Medicine, Josep Carreras Leukemia Research Institute, University of Barcelona, 08036, Barcelona, Spain.
(6)Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield, S10 2RX, UK.
(7)Department of Biotechnology and Nanomedicine, SINTEF Industry, 7465, Trondheim, Norway.
(8)Spanish Network on Rare Diseases
(CIBERER), 28029, Madrid, Spain.
(9)Human Genotyping-CEGEN Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre
(CNIO), 28029, Madrid, Spain.
(10)Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre
(CNIO), 28029, Madrid, Spain. [Email]
(11)Spanish Network on Rare Diseases
(CIBERER), 28029, Madrid, Spain. [Email]
(#)Contributed equally

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.