The role of DNA damage and repair at telomeres

National Institute On Aging

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Abstract

We have investigated whether telomeres are prone to oxidative DNA damage. In comparison to non-telomeric DNA, telomeric DNA harbors more oxidative base lesions, which is likely due to inefficient DNA repair at telomeres. Oxidative stress may result in a variety of DNA damages. Oxidative DNA base lesions are primarily repaired by base excision repair (BER). The initial step in BER is removal of the damaged base by a DNA glycosylase. Mammalian cells express several DNA glycosylases with overlapping, yet distinct specificities for different oxidative DNA lesions. We have initiated an investigation into the molecular mechanisms through which oxidative base lesions and DNA glycosylase deficiency affect telomere length/function. Previously we have examined the impact of oxidative guanine base lesions at telomeres in budding yeast and mice. We also found that a key BER protein, Ogg1 DNA glycosylase is critical in oxidative guanine base repair. Because oxidative stress can also cause oxidative modifications at pyrimidine bases, we have investigated if oxidative pyrimidine damage could accumulate at telomeres. We employed a mouse model with a loss in the Nth1 DNA glycosylase that excises oxidized pyrimidines. Nth1 deficiency leads to an increase in oxidative pyrimidine lesions at telomeres in mouse tissues and primary cells, suggesting that Nth1 is critical in repairing oxidative pyrimidine damage in telomeric DNA in mammalian cells. Ablation of Nth1 function results in telomere attrition and telomere strand breaks that are dependent on an environmental oxidative exposure. These results suggest that Nth1 plays an important role in telomere base repair and telomere maintenance against oxidative stress-induced DNA damage. The work was recently publisehd in Plos Genetics. Our long term goal is to investigate the role of oxidative base damage and BER deficiency in telomere damage-induced cellular senescence and organismal aging, particularly using mouse strains that mimic humans with regard to telomere length and telomerase activity. The will serve as useful guidelines for future studies that employ human cells.