Telomere dysfunction results in enhanced organismal sensitivity to the alkylating agent N-methyl-N-nitrosourea.
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.
González-Suárez
Eva
E
Department of Immunology and Oncology, National Center of Biotechnology, Madrid, Spain.
Goytisolo
Fermín A
FA
Flores
Juana M
JM
Blasco
María A
MA
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D005260:Female; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D016615:Telomere / Q000502:physiology*
D000477:Alkylating Agents; D008770:Methylnitrosourea; D019098:Telomerase