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Telomere Dysfunction and DNA-PKcs Deficiency: Characterization and Consequence

¹ Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado; ² Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institution, Tampa, Florida; ³ Center for Radiological Research, Columbia University, Irvington, New York; ⁴ Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; ⁵ Medizinisches Proteom-Center, Ruhr Universität Bochum, Bochum, Germany; ⁶ Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada; and ⁷ College of Veterinary Medicine, Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan

Requests for reprints: Susan M. Bailey, Colorado State University, Campus Delivery 1618, Fort Collins, CO 80523-1618. Phone: 970-491-2944; Fax: 970-491-7742; E-mail: sbailey{at}colostate.edu.

Key Words: telomeres • DNA-PKcs • carcinogenesis • genomic instability • ionizing radiation

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 nonhomologous end-joining (NHEJ) protein DNA-dependent protein kinase (DNA-PK) in the effective end-capping of mammalian telomeres. 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-PKcs) 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 event 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 cancer. 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. [Cancer Res 2009;69(5):2100–7]

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