Telomere dysfunction and DNA-PKcs deficiency: Characterization and consequence

Eli S. Williams, Rebekah Klingler, Brian Ponnaiya, Tanja Hardt, Evelin Schrock, Susan P. Lees-Miller, Katheryn Meek, Robert L. Ullrich, Susan M. Bailey

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

The mechanisms by which cells accurately distinguish between DNA double-strand break (DSB) ends and telomeric DNA ends remain poorly defined. Recent investigations have revealed intriguing interactions between DNA repair and telomeres. We were the first to report a requirement for the onhomologous end-joining (NHEJ) protein DNA-dependent protein kinase (DNA-PK) in the effective end-capping of mammalian telo-meres. Here, we report our continued characterization of uncapped (as opposed to shortened) dysfunctional telomeres in cells deficient for the catalytic subunit of DNA-PK (DNA-FKcs) and shed light on their consequence. We present evidence in support of our model that uncapped telomeres in this repair-deficient background are inappropriately detected and processed as DSBs and thus participate not only in spontaneous telomere-telomere fusion but, importantly, also in ionizing radiation-induced telomere-DSB fusion events. We show that phosphorylation of DNA-PKcs itself (Thr-2609 cluster) is a critical evt for proper telomere end-processing and that ligase IV (NHEJ) is required for uncapped telomere fusion. We also find uncapped telomeres in cells from the BALB/c mouse, which harbors two single-nucleotide polymorphisms that result in reduced DNA-PKcs abundance and activity, most markedly in mammary tissue, and are both radiosensitive and susceptible to radiogenic mammary can-cer. Our results suggest mechanistic links between uncapped/ dysfunctional telomeres in DNA-PKcs-deficient backgrounds, radiation-induced instability, and breast cancer. These studies provide the first direct evidence of genetic susceptibility and environmental insult interactions leading to a unique and ongoing form of genomic instability capable of driving carcinogenesis.

Original languageEnglish (US)
Pages (from-to)2100-2107
Number of pages8
JournalCancer Research
Volume69
Issue number5
DOIs
StatePublished - Mar 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Williams, E. S., Klingler, R., Ponnaiya, B., Hardt, T., Schrock, E., Lees-Miller, S. P., Meek, K., Ullrich, R. L., & Bailey, S. M. (2009). Telomere dysfunction and DNA-PKcs deficiency: Characterization and consequence. Cancer Research, 69(5), 2100-2107. https://doi.org/10.1158/0008-5472.CAN-08-2854