The role of telomere dysfunction in driving genomic instability

Susan M. Bailey, Eli S. Williams, Robert L. Ullrich

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)146-149
Number of pages4
JournalInternational Congress Series
Volume1299
DOIs
StatePublished - Feb 1 2007

Keywords

  • DNA-repair
  • Radiation carcinogenesis
  • Telomere

ASJC Scopus subject areas

  • Medicine(all)

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