Cristin-resultat-ID: 1942650
Sist endret: 24. januar 2022, 09:25
NVI-rapporteringsår: 2021
Resultat
Vitenskapelig artikkel
2021

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

Bidragsytere:
  • Juan Miguel Baquero
  • Carlos Benitez-Buelga
  • Varshni Rajagopal
  • Zhao Zhenjun
  • Raúl Torres-Ruiz
  • Sarah Müller
  • mfl.

Tidsskrift

Scientific Reports
ISSN 2045-2322
e-ISSN 2045-2322
NVI-nivå 1

Om resultatet

Vitenskapelig artikkel
Publiseringsår: 2021
Publisert online: 2021
Volum: 11
Artikkelnummer: 3490
Open Access

Importkilder

Scopus-ID: 2-s2.0-85100952404

Beskrivelse Beskrivelse

Tittel

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

Sammendrag

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.

Bidragsytere

Juan Miguel Baquero

  • Tilknyttet:
    Forfatter
    ved Centro Nacional de Investigaciones Oncológicas

Carlos Benitez-Buelga

  • Tilknyttet:
    Forfatter
    ved Karolinska Institutet

Varshni Rajagopal

  • Tilknyttet:
    Forfatter
    ved Karolinska Institutet

Zhao Zhenjun

  • Tilknyttet:
    Forfatter
    ved Karolinska Institutet

Raúl Torres-Ruiz

  • Tilknyttet:
    Forfatter
    ved Universitat de Barcelona
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