MSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeres.
Mutations in the mismatch repair (MMR) pathway occur in human colorectal cancers with microsatellite instability. Mounting evidence suggests that cell-cycle arrest in response to a number of cellular stresses, including telomere shortening, is a potent anticancer barrier. The telomerase-deficient mouse model illustrates the anticancer effect of cell-cycle arrest provoked by short telomeres. Here, we describe a role for the MMR protein, MSH2, in signaling cell-cycle arrest in a p21/p53-dependent manner in response to short telomeres in the context of telomerasedeficient mice. In particular, progressively shorter telomeres at successive generations of MSH2(-/-) Terc(-/--) mice did not suppress cancer in these mice, indicating that MSH2 deficiency abolishes the tumor suppressor activity of short telomeres. Interestingly, MSH2 deficiency prevented degenerative pathologies in the gastrointestinal tract of MSH2(-/-) Terc(-/-) mice concomitant with a rescue of proliferative defects. The abolishment of the anticancer and pro-aging effects of short telomeres provoked by MSH2 abrogation was independent of changes in telomere length. These results highlight a role for MSH2 in the organismal response to dysfunctional telomeres, which in turn may be important in the pathobiology of human cancers bearing mutations in the MMR pathway.
Martinez
Paula
P
Spanish National Cancer Centre, Madrid, Spain.
Siegl-Cachedenier
Irene
I
Flores
Juana M
JM
Blasco
Maria A
MA
D000375:Aging / Q000235:genetics*; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D043171:Chromosomal Instability; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007421:Intestine, Small / Q000473:pathology; D008017:Life Expectancy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D051718:MutS Homolog 2 Protein / Q000172:deficiency*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D019098:Telomerase / Q000172:deficiency; D016615:Telomere / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D019098:Telomerase; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein