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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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National Institute on Aging
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Long, Juanjuan; Huang, Chenhui; Chen, Yanyan et al. (2017) Telomeric TERB1-TRF1 interaction is crucial for male meiosis. Nat Struct Mol Biol 24:1073-1080
Sarkar, Jaya; Liu, Yie (2016) Fanconi anemia proteins in telomere maintenance. DNA Repair (Amst) 43:107-12
Sarkar, Jaya; Wan, Bingbing; Yin, Jinhu et al. (2015) SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nucleic Acids Res 43:5912-23
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Popuri, Venkateswarlu; Hsu, Joseph; Khadka, Prabhat et al. (2014) Human RECQL1 participates in telomere maintenance. Nucleic Acids Res 42:5671-88
Shi, Jianxin; Yang, Xiaohong R; Ballew, Bari et al. (2014) Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 46:482-6
Vallabhaneni, Haritha; O'Callaghan, Nathan; Sidorova, Julia et al. (2013) Defective repair of oxidative base lesions by the DNA glycosylase Nth1 associates with multiple telomere defects. PLoS Genet 9:e1003639
Lu, Jian; Vallabhaneni, Haritha; Yin, Jinhu et al. (2013) Deletion of the major peroxiredoxin Tsa1 alters telomere length homeostasis. Aging Cell 12:635-44
Ghosh, Avik K; Rossi, Marie L; Singh, Dharmendra Kumar et al. (2012) RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance. J Biol Chem 287:196-209
McNeill, Daniel R; Lin, Ping-Chang; Miller, Marshall G et al. (2011) XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility. Nucleic Acids Res 39:7992-8004

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