Edwin H. Goodwin and Susan M. Bailey
Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM
Telomeres are an often under-appreciated element in preserving genomic stability because, under most circumstances, they protect chromosome ends extremely well. When telomere dysfunction occurs, the consequences are severe. They include the induction of cellular senescence, and chromosomal rearrangements that may promote carcinogenesis. The molecular basis of telomere function is only now coming to light. Previously we demonstrated that effective capping of mouse telomeres has a paradoxical requirement for proteins more commonly associated with DNA DSB repair. These are Ku70, Ku80, and DNA-PKcs (the catalytic subunit of DNA protein kinase). These proteins, the constituents of DNA-PK, participate in DSB repair by non-homologous end-joining. Mutations in any of these genes cause spontaneous chromosomal end-to-end fusions that contribute significantly to the background level of chromosomal aberrations (Bailey et al., PNAS 96 (1999) 14899). Recently we find that impaired end-capping also allows telomeres to join to ends created by radiation-induced DSB. DNA-PKcs-deficient mouse cells were exposed to gamma ray doses of 0 to 115cGy. A specialized cytogenetic technique was used to distinguish true telomere-to-DSB events from telomere-to-telomere fusions. Both types of events were observed in DNA-PKcs-deficient cells but not repair-proficient controls. Chromosome aberrations created by telomere-to-DSB fusion rivaled the frequency of ordinary exchange-type aberrations. These results demonstrate for the first time that telomeres in cells with DNA-PKcs deficiency can fuse to radiation-induced DSB ends to create novel chromosome structural arrangements. Thus the radiation-sensitive phenotype associated with DNA-PKcs deficiency is not due solely to ineffective DSB repair. Rather, telomere-to-DSB joining provides an additional pathway for misrepair not existing in repair-proficient cells. Furthermore, impaired telomere function, as a new source of chromosomal instability, should be examined closely as a possible contributor to the cancer-prone phenotype associated with DSB-repair deficiency. We thank Gloria Li, Sandeep Burma, Akihiro Kurimasa and David Chen for cell lines, and the DOE and US Army for funding.