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DNA Damage and Cellular Stress Responses

Telomere Instability in a Human Tumor Cell Line Expressing NBS1 With Mutations at Sites Phosphorylated by ATM¹

Radiation Oncology Research Laboratory, University of California, San Francisco, San Francisco, CA

Requests for reprints: John P. Murnane, Radiation Oncology Research Laboratory, University of California, San Francisco, 1855 Folsom Street, MCB 200, San Francisco, CA 94103. Phone: (415) 476-9083; Fax: (415) 476-9069. E-mail: murnane{at}radonc17.ucsf.edu

Nijmegen breakage syndrome (NBS) is an autosomal genetic disease demonstrating a variety of phenotypic abnormalities, including premature aging, increased cancer incidence, chromosome instability, and sensitivity to ionizing radiation. The gene involved in NBS, NBS1, is part of the MRE11/RAD50/NBS1 (MRN) complex that also includes MRE11 and RAD50, which is involved in DNA repair and cell cycle regulation in response to DNA damage. The MRN complex is also involved in telomere maintenance, as demonstrated by the shortened telomeres in NBS primary human fibroblasts and the association of NBS1 with the telomere-binding protein TRF2. To learn more about how a deficiency in telomere maintenance might contribute to chromosome instability in NBS, we have investigated the stability of telomeres in two telomerase-positive human tumor cell clones, BNmt-On and BNmt-Off, expressing an inducible NBS1^S278A/S343A gene containing mutations at serines 278 and 343 phosphorylated by ATM. The results demonstrate an increased rate of telomere loss in both clones following expression of NBS1^S278A/S343A. The absence of detectable changes in average telomere length suggests that NBS1-associated telomere loss results from stochastic events involving complete telomere loss or loss of telomere capping function. The recombination events associated with telomere loss were found to be similar to those shown previously to result in breakage/fusion/bridge cycles, suggesting that telomere loss can contribute to chromosome instability in NBS1-deficient cells. Telomere loss showed no correlation with radiosensitivity or radioresistant DNA synthesis, demonstrating that NBS1^S278A/S343A promotes telomere loss through a separate pathway from these other phenotypes associated with NBS.

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