Martinez Paula, Siegl-Cachedenier Irene, Flores Juana M, Blasco Maria A
Spanish National Cancer Centre, Madrid, Spain.
Aging Cell. 2009 Feb;8(1):2-17. doi: 10.1111/j.1474-9726.2008.00441.x.
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.
错配修复（MMR）途径中的突变发生在具有微卫星不稳定性的人类结直肠癌中。越来越多的证据表明，细胞对包括端粒缩短在内的多种细胞应激产生的细胞周期停滞是一种强大的抗癌屏障。端粒酶缺陷小鼠模型说明了短端粒引发的细胞周期停滞的抗癌作用。在此，我们描述了MMR蛋白MSH2在端粒酶缺陷小鼠背景下，以p21/p53依赖的方式响应短端粒时发出细胞周期停滞信号中的作用。特别是，在连续几代的MSH2（-/-）Terc（-/-）小鼠中，端粒逐渐缩短并未抑制这些小鼠中的癌症，这表明MSH2缺陷消除了短端粒的肿瘤抑制活性。有趣的是，MSH2缺陷预防了MSH2（-/-）Terc（-/-）小鼠胃肠道的退行性病变，同时挽救了增殖缺陷。MSH2缺失引发的短端粒的抗癌和促衰老作用的消除与端粒长度的变化无关。这些结果突出了MSH2在机体对功能失调端粒的反应中的作用，这反过来可能在携带MMR途径突变的人类癌症的病理生物学中很重要。
