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those from the TTD mouse or the Xpa mouse separately, have increased sensitivi-ty to the poison paraquat or ionizing radia-tion. Both of these agents damage DNA, generating some of the same lesions as ROS, which lends support to the possibili-ty that ROS-induced lesions initiate the age-related decline in TTD mice. The authors propose that a response to stalled transcription at sites of DNA dam-age is responsible for early aging in TTD mice. In this scenario, a defective TFIIH re-sults in stalled transcription that decreases gene activity and leads to a mild accumula-tion of DNA damage. Cells respond by un-dergoing either apoptosis (programmed cell death) or cellular senescence (irreversible cessation of cell division), both of which may contribute to early organismal senes-cence in TTD mice. In the absence of Xpa alone (that is, with a fully functional Xpd protein), transcription from a damaged DNA template can still take place, possibly because the amount of spontaneous damage subject to NER is low. In combination with TTD, however, the complete absence of Xpa would exacerbate the suboptimal per-formance of TFIIH, leaving the DNA lesion exposed for a greater period of time; this would result in a further decline in gene ac-tivities and an enhanced response. Thus, early senescence in the TTD mouse may be primarily the result of a cellular response to impaired TFIIH at the site of a spontaneous DNA lesion, rather than the accelerated ac-cumulation of DNA damage or mutations. Although the true nature of the prema-ture aging phenomenon in the TTD mouse is not yet completely understood, there is support for the scenario sketched above. For example, Ku86 knockout mice, which are completely defective in nonhomolo-gous end joining of double-strand DNA breaks, display various symptoms of ac-celerated aging (9). At least part of this phenotype is dependent on p53 (10), a tu-mor suppressor protein crucial for the cel-lular response to DNA damage that leads to apoptosis or cellular senescence. Inter-estingly, mice with increased p53 activity exhibit premature senescence (11). This supports the notion that at least a part of organismal aging is due to cell death o

Year: 2016
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