The role of DNA damage and repair at telomeres

National Institute On Aging

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Abstract

Reactive oxygen species (ROS) are the byproducts of normal cellular respiration or as a result of environmental exposure to physical and chemical agents, e.g. ionizing radiation. ROS can result in a variety of oxidative damages to cellular components, and contribute to organism aging. Peroxiredoxins (Prxs) catalyze peroxide reduction of ROS. We are investigating if Prx deficiency can affect telomere integrity. Our preliminary results suggest that ROS may drive telomere mutagenesis and perturb the pathways involved in telomere length regulation. We are also investigating the role of several oxidative base damage repair proteins, including Endonuclease III-like protein 1 (Nth1) in telomere length maintenance. We found that NTH1 defective mice show accelerated telomere shortening. Furthermore, telomere length abnormalities were accompanied by telomere replication defects. These findings indicate that oxidative base damage can affect telomere length homeostasis. Our studies demonstrate that BER proteins are required in maintaining telomere integrity in mammals. We will continue to explore the impact of other DNA glycosylases (i.e. 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 have investigated whether telomeres are more sensitive to oxidative base damage in comparison to non-telomeric DNA. We have also explored 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 data suggests that telomere DNA repeats are more prone to oxidative damage and repaired less efficiently than non-telomeric TG repeats. The certain telomere configurations may contribute to telomere vulnerability to oxidative DNA damage processing. However, telomere binding factors do not affect BER repair using in vitro testing. We are revising experimental approach that allows us to test the impact of telomere specific factors on oxidative DNA damage and repair in cells.