The role of DNA damage and repair at telomeres

National Institute On Aging

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Abstract

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.