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Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease

机译:端粒功能障碍诱导Sirtuin抑制,推动端粒依赖性疾病

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Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.
机译:端粒缩短与干细胞下降,纤维化障碍和过早老化,通过不完全理解的机制。在这里,我们表明端粒酶敲除小鼠肝脏的端粒体缩短导致所有七个SIRTUIN的P53依赖性抑制。 P53通过微小RNA(miR-36a,26a和145)调节转录的非线粒体sirtuins(sirt1,2,6和7),而线粒体sirtuins(sirt3,4和5)在过氧化物酶体增殖物中受到调节 - 在转录水平下活化受体γ共激活剂1α/β依赖性方式。施用NAD(+)前体烟酰胺单核苷酸保持端粒长度,抑制DNA损伤反应和P53,改善线粒体功能,并且在功能上,以部分SIRT1依赖性方式拯救肝纤维化。这些研究建立了SIRTUINS作为功能障碍端粒的下游靶标,并表明单独增加SIRT1活性或与其他SIRTUIN的组合稳定端粒并减轻端粒依赖性疾病。

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