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首页> 外文期刊>Aging cell. >MSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeres.
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MSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeres.

机译：MSH2缺乏消除了短端粒的抗癌和抗衰老活性。

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摘要

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.
机译：不匹配修复（MMR）途径的突变发生在具有微卫星不稳定性的人大肠癌中。越来越多的证据表明，响应许多细胞应激（包括端粒缩短）的细胞周期停滞是有效的抗癌屏障。端粒酶缺陷型小鼠模型说明了由短端粒引起的细胞周期停滞的抗癌作用。在这里，我们描述了MMR蛋白MSH2在端粒酶缺乏小鼠的情况下以对短端粒的响应以p21 / p53依赖性方式信号传导细胞周期停滞的作用。特别是，在连续几代MSH2（-/-）Terc（-/-）小鼠中逐渐变短的端粒不能抑制这些小鼠的癌症，这表明MSH2缺乏消除了短端粒的肿瘤抑制活性。有趣的是，MSH2缺乏症可预防MSH2（-/-）Terc（-/-）小鼠胃肠道的退行性病变，并能挽救增殖性缺陷。 MSH2废除引起的短端粒的抗癌作用和衰老作用的消除与端粒长度的变化无关。这些结果突显了MSH2在机体对功能失调的端粒的应答中的作用，这反过来在携带MMR途径突变的人类癌症的病理学中可能很重要。

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