Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress.

Mariarosaria De Rosa,Patricia L Opresko,Samuel A Johnson

doi:10.3389/fcell.2021.758402

Mariarosaria De Rosa, Patricia L Opresko + Show 1 more

Open Access

https://doi.org/10.3389/fcell.2021.758402

Copy DOI

Abstract

Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can contribute to either cellular senescence and aging, or tumorigenesis. Human reproductive cells, some stem cells, and most cancer cells, express the enzyme telomerase to restore telomeric DNA. Numerous studies have shown that oxidative stress caused by excess reactive oxygen species is associated with accelerated telomere shortening and dysfunction. Telomeric repeat sequences are remarkably susceptible to oxidative damage and are preferred sites for the production of the mutagenic base lesion 8-oxoguanine, which can alter telomere length homeostasis and integrity. Therefore, knowledge of the repair pathways involved in the processing of 8-oxoguanine at telomeres is important for advancing understanding of the pathogenesis of degenerative diseases and cancer associated with telomere instability. The highly conserved guanine oxidation (GO) system involves three specialized enzymes that initiate distinct pathways to specifically mitigate the adverse effects of 8-oxoguanine. Here we introduce the GO system and review the studies focused on investigating how telomeric 8-oxoguanine processing affects telomere integrity and overall genome stability. We also discuss newly developed technologies that target oxidative damage selectively to telomeres to investigate roles for the GO system in telomere stability.

Highlights

TELOMERES ON THE guanine oxidation (GO)Telomere caps at the ends of linear chromosomes are nucleoprotein-DNA structures essential for genome stability, sustained cellular proliferation, and the overall health of an organism
Telomeres lie at the interface between aging and cancer because dysfunctional telomeres contribute to degenerative diseases that occur with aging, and cause genetic alterations that drive carcinogenesis [reviewed in (Chakravarti et al, 2021)]
This study reported the novel discovery that loss of OGG1 increased telomeric 8oxo-G in primary mouse embryonic fibroblasts (MEFs) under high oxidative stress conditions, and increased telomere attrition and aberrations (Wang et al, 2010). These findings provide evidence that OGG1 is involved in the repair of oxidative guanine lesions in telomeres in vivo, and that low basal telomeric 8-oxoG levels are associated with telomere lengthening in unstressed mice

Summary

Introduction

TELOMERES ON THE GOTelomere caps at the ends of linear chromosomes are nucleoprotein-DNA structures essential for genome stability, sustained cellular proliferation, and the overall health of an organism. Too much 8-oxoG arising from oxidative stress is clearly detrimental, and causes telomere shortening and aberrations in repair-deficient cultured cells.

Results

Conclusion