The Role of Telomere Dysfunction in Driving Genomic Instability

摘要: The mechanistic role of radiation-induced genomic instability in radiation carcinogenesis is an attractive hypothesis that remains to be rigorously tested. There are few vivo studies on which base judgments, but work our laboratory with mouse models radiogenic mammary neoplasia provided the first indications certain forms genetically predisposed may contribute tumor development. Most recently, we have focused induction telomere dysfunction following exposure ionizing and DNA-PKcs this process. In present studies, characterization dysfunctional telomeres DNA-PKcs-defi cient backgrounds, including BALB/ c, provides evidence supporting model these uncapped behave as double-strand breaks (DSBs), despite presence ample telomeric sequence. Further, demonstrate inappropriate interstitial sequence at sites DSBs involves nonhomologous end-joining (NHEJ) pathway autophosphorylation plays important role. Thus, impaired function, a significant source spontaneous chromosomal instability, has potential cancer-prone phenotype associated even partial DSB repair defi ciency.