The role of telomere dysfunction in driving genomic instability

Abstract

Radiation-induced genomic instability as an initiating event in radiation carcinogenesis is an attractive hypothesis that remains to be rigorously tested. Our studies have focused on the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in this process. We have shown that effective telomeric end capping of mammalian chromosomes requires proteins more commonly associated with double-strand break (DSB) repair. Impaired end capping in DNA-PKcs-deficient genetic backgrounds not only allows dysfunctional telomeres to fuse to each other (telomere–telomere fusion), but also to broken chromosome ends created by radiation-induced DSBs (telomere–DSB fusion). Interstitial telomere sequences have been shown to be an inherent source of instability. It is also noteworthy that telomere–DSB fusions remove just one of the two ends created by a DSB, thereby rendering the remaining broken end capable of driving on-going chromosomal instability. We have used mouse Spectral Karyotyping and telomere chromosome orientation fluorescence in situ hybridization (CO-FISH) to reveal a clonal translocation possessing a telomere–DSB signal at the translocation breakpoint. Another approach has been to analyze radiation-altered cells using BAC-CGH array technology. DNA-PKcs deficient BALB/c mouse mammary vs. mammary tumor DNA revealed an amplification on chromosome 11 that has synteny to human 17q 25.1, a region frequently amplified in breast carcinoma. These studies continue to support our hypothesis that impaired telomeric function is a significant source of radiation-induced chromosomal instability that has the potential of contributing to the cancer-prone phenotype associated with even partial DSB repair deficiency.