Bone Aging in DNA Repair Deficient Trichothiodystrophy Mice

Abstract

Our genome is continuously damaged by environmental, endogenous agents as well as by the instrinsic instability of DNA. For example, UV light gives rise to helix-distorting cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6,4)-pyrimidone adducts (6-4PPs). Ionizing radiation can cause both single and double strand breaks in DNA and numerous types of oxidative lesions. Chemotherapeutics, that are used in cancer therapy, and other environmental chemical agents, which are present in e.g. polluted air and tobacco smoke, induce a plethora of DNA lesions, including intra- and inter-strand cross-links and mono-adducts. In addition, endogenous agents cause a wide variety of DNA lesions. Metabolic processes within our cells lead to reactive oxygen species (ROS), which react with proteins, lipids and DNA. Although ROS participate in beneficial physiological processes as growth factor signal transduction, these by-products of metabolism also underlie a broad spectrum of oxidative DNA lesions, including 8-oxo-2’-deoxyguanosine (8-oxodG), thymine glycols, cylcopurines, as well as single and double strand breaks. Finally, lesions in the DNA can also form without a direct damaging agent. E.g. spontaneous hydrolysis or modifications of nucleotides occurs in cells, which leaves non-informative a-basic sites or altered, miscoding nucleotides