Abstract
Telomeres are nucleoprotein structures that maintain genomic stability by protecting the ends of linear chromosomes. In striking contrast to natural chromosomal termini, broken chromosome ends produced by DNA double strand breaks (DSBs) are highly recombinogenic, and represent a major threat to the integrity of the cell's genome due to their potential for causing chromosomal rearrangements that contribute to genomic instability and tumorigenesis. We've demonstrated that effective end-capping of mammalian telomeres has a seemingly paradoxical requirement for proteins more commonly associated with DNA DSB repair. Ku70, Ku86, and DNA-PKcs all participate in DSB repair through non-homologous end-joining. Mutations in any of these genes cause spontaneous chromosomal end-to-end fusions that maintain large blocks of telomeric sequence at the points of fusion that are not a consequence of telomere shortening. We've also shown that nascent telomeres produced via leading-strand DNA synthesis are especially susceptible to these end-to-end fusions. Here we report that impaired end-capping also allows dysfunctional telomeres to misjoin to broken chromosome ends created by radiation-induced DSB. [J Radiat Res 44:374 (2003)]
