Deficient mismatch repair improves organismal fitness and survival of mice with dysfunctional telomeres.
Mismatch repair (MMR) has important roles in meiotic and mitotic recombination, DNA damage signaling, and various aspects of DNA metabolism including class-switch recombination, somatic hypermutation, and triplet-repeat expansion. Defects in MMR are responsible for human cancers characterized by microsatellite instability. Intriguingly, MMR deficiency has been shown to rescue survival and proliferation of telomerase-deficient yeast strains. A putative role for MMR at mammalian telomeres that could have an impact on cancer and aging is, however, unknown. Here, we studied the role of MMR in response to dysfunctional telomeres by generating mice doubly deficient for telomerase and the PMS2 MMR gene (Terc-/-/PMS2-/- mice). PMS2 deficiency prolonged the mean lifespan and median survival of telomerase-deficient mice concomitant with rescue of degenerative pathologies. This rescue of survival was independent of changes in telomere length, in sister telomere recombination, and in microsatellite instability. Importantly, PMS2 deficiency rescued cell proliferation defects but not apoptotic defects in vivo, concomitant with a decreased p21 induction in response to short telomeres. The proliferative advantage conferred to telomerase-deficient cells by the ablation of PMS2 did not produce increased tumors. Indeed, Terc-/-/PMS2-/- mice showed reduced tumors compared with PMS2-/- mice, in agreement with a tumor suppressor role for short telomeres in the context of MMR deficiencies. These results highlight an unprecedented role for MMR in mediating the cellular response to dysfunctional telomeres in vivo by attenuating p21 induction.
Siegl-Cachedenier
Irene
I
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid 28029, Spain.
Muñoz
Purificación
P
Flores
Juana M
JM
Klatt
Peter
P
Blasco
María A
MA
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D008017:Life Expectancy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053842:Microsatellite Instability; D000070976:Mismatch Repair Endonuclease PMS2; D009374:Neoplasms, Experimental / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D011995:Recombination, Genetic; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics; D016615:Telomere / Q000502:physiology*