We have investigated the impact of oxidative guanine lesions on telomere integrity and the role of their repair enzymes, 8oxoguanine DNA glycosylase 1 (OGG1) in telomere length maintenance. We found that oxidative guanine lesions accumulated in telomeres in OGG1 defective budding yeast and mice and that the amount of oxidative base lesions increased in mouse tissues during aging. These guanine lesions led to changes in telomere length. Furthermore, telomere length abnormalities were accompanied by altered telomere recombination, increased telomere single and double strand breaks, and preferential telomere G-strand losses. These findings indicate that oxidative base damage can arise in telomeres and affect telomere length homeostasis, recombination, and DNA breakage repair. Our studies demonstrate that BER pathway is required in repairing oxidative base damage in telomeres and maintaining telomere integrity in budding yeast and mammals. We will continue to explore the impact of other oxidative base lesions (i.e. pyrimidines) and DNA glycosylases (i.e. NTH1 and NEIL1) on telomere length and function. Because telomeres significantly contribute to the overall genome stability and telomere dysfunction can result in chromosome fusions, breakages, and genome instability, we are investigating whether telomeres are more sensitive to oxidative base damage in comparison to non-telomeric DNA. We are also exploring if telomere specific factors (e.g. telomere repeat sequences, telomere associated proteins and telomere specific structures) may influence oxidative base damage and repair in telomeres. Our preliminary work suggests that telomere DNA repeats are more prone to oxidative guanine damage and repaired less efficiently than non-telomeric TG repeats in vivo. The sequence context of telomere repeats and certain telomere configurations may contribute to telomere vulnerability to oxidative DNA damage processing.
| 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 |
| Vallabhaneni, Haritha; Zhou, Fang; Maul, Robert W et al. (2015) Defective repair of uracil causes telomere defects in mouse hematopoietic cells. J Biol Chem 290:5502-11 |
| 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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