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

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.

Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening

“…OGG1 first removes 8oxoG, then APE1 cleaves the backbone and scaffold protein XRCC1 arrives to coordinate repair 32 . To verify 8oxoG formation, we showed increased YFP-XRCC1 colocalization and signal intensity at telomeres after dye and light (DL) that was attenuated in OGG1 knockout cells (ko) or with 1 O 2 quencher sodium azide (Fig.…”

“…1 O 2 is a main contributor of UVA radiation-induced oxidation reactions, arises from inflammation, lipoxygenases and dioxygenases, and forms primarily 8oxoG when reacting with DNA 30 , 31 . The physiological importance of 8oxoG is underscored by the evolution of three dedicated enzymes that specifically recognize 8oxoG in various contexts to enable repair and prevent mutations 32 , 33 . We used a FAP-mCerulean-TRF1 fusion protein to target 1 O 2 to telomeres 28 .…”

Targeting the DNA repair enzymes MTH1 and OGG1 as a novel approach to treat inflammatory diseases

“…This can lead to the formation of an 8‐oxoG·A pair from 8‐oxoG·C during a first round of replication, and after a second round to a T·A pair instead of the original G·C. To avoid this, 8‐oxoG can be excised by the DNA glycosylase OGG1 before replication, or alternatively, the erroneous adenine can be removed by another glycosylase, the MutY homologue 20 . Thus, OGG1 is of great importance for the cells due to its role in excising 8‐oxoG from the DNA, therefore limiting mutations and strand breaks.…”

“…To avoid this, 8-oxoG can be excised by the DNA glycosylase OGG1 before replication, or alternatively, the erroneous adenine can be removed by another glycosylase, the MutY homologue. 20 Thus, OGG1 is of great importance for the cells due to its role in excising 8-oxoG from the DNA, therefore limiting mutations and strand breaks.…”

Senescence in Vascular Smooth Muscle Cells and Atherosclerosis

“…Oxidative stress has also been shown to cause accelerated telomere shortening as it is rich in guanine and therefore prone to prone to be oxidized to 8oxoG ( 35 ). Telomere shortening was strongly associated with increasing severity of atherosclerosis, and telomere length was a putative risk factor for atherosclerotic cardiovascular disease ( 36 , 37 ).…”