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Telomere Dysfunction Results in Enhanced Organismal Sensitivity to the Alkylating Agent N-Methyl-N-Nitrosourea¹

Department of Immunology and Oncology, National Center of Biotechnology [E. G. S., F. A. G., M. A. B.], and Animal Pathology II, Facultad de Veterinaria, Universidad Complutense de Madrid [J. M. F.], Madrid, Spain

Here, we use telomerase-deficient mice, Terc^-/-, to study the impact of telomerase abrogation in response to treatment with the alkylating agent N-Methyl-N-Nitrosourea (MNU), a potent carcinogen in the mouse. Wild-type mice treated with MNU developed lymphomas and carcinomas. In contrast, similarly treated G5 Terc^-/- mice with critically short telomeres did not develop tumors and died of acute toxicity to the small intestine. G2 Terc^-/- mice, which have long telomeres, were less susceptible to MNU-induced tumors than wild-type mice, as well as less sensitive to MNU toxicity than G5 Terc^-/- mice. The results indicate that short telomeres suppress tumor growth and that lack of telomerase retards tumor progression, even in the presence of long telomeres. Finally, G5 Terc^-/- hypersensitivity to MNU supports the notion that short telomeres interfere with proper DNA damage repair.

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