衰老是人和動(dòng)物都無(wú)法避免的生理過(guò)程,，真核細(xì)胞在衰老的過(guò)程中基因組會(huì)變得失去穩(wěn)定性，基因表達(dá)也會(huì)基因組的不穩(wěn)定性而發(fā)生改變,。研究發(fā)現(xiàn),，酵母細(xì)胞中的組蛋白脫乙酰基酶Sir2具有沉默轉(zhuǎn)錄子和穩(wěn)定重復(fù)DNA的功效,，但是,，當(dāng)細(xì)胞開(kāi)始老化或是DNA斷裂情況發(fā)生的時(shí)候，Sir復(fù)合物會(huì)失去原來(lái)的功能,，變得不具有沉默基因的能力,，并最終導(dǎo)致酵母失去自我增殖的能力，這是酵母老化過(guò)程中伴隨發(fā)生的典型特征,。
為了解哺乳動(dòng)物是否具有相似的情況,，研究者用小鼠胚胎干細(xì)胞來(lái)進(jìn)行試驗(yàn)，結(jié)果發(fā)現(xiàn)SIRT1的功能與酵母的Sir2相似，SIRT1具有抑制重復(fù)DNA片段各種基因表達(dá)的功能,。當(dāng)DNA發(fā)生斷裂的情況時(shí),，SIRT1就會(huì)從基因組轉(zhuǎn)座子上掉落，并重新定位促進(jìn)DNA修復(fù),，改變轉(zhuǎn)錄過(guò)程,，這一情況在老化的細(xì)胞中同樣會(huì)出現(xiàn)。如果增加SIRT1的表達(dá)量可有效保護(hù)基因組穩(wěn)定性遭破壞的細(xì)胞維持活性,，抑制老化帶來(lái)的基因組轉(zhuǎn)錄變化,。
所以說(shuō)，DNA造到破壞可誘導(dǎo)SIRT1重新分配,，并隨之改變基因組的轉(zhuǎn)錄情況,，改變蛋白的表達(dá)情況，這一機(jī)制可能是真核細(xì)胞在老化過(guò)程中一個(gè)保守的機(jī)制,。（生物谷Bioon.com）
生物谷推薦原始出處：
Cell, Volume 135, Issue 5, 907-918, 28 November 2008 doi:10.1016/j.cell.2008.10.025
SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression during Aging
Philipp Oberdoerffer1,Shaday Michan1,Michael McVay1,Raul Mostoslavsky2,James Vann3,Sang-Kyu Park3,Andrea Hartlerode4,Judith Stegmuller1,7,Angela Hafner1,Patrick Loerch1,Sarah M. Wright5,Kevin D. Mills5,Azad Bonni1,Bruce A. Yankner1,Ralph Scully4,Tomas A. Prolla3,Frederick W. Alt6andDavid A. Sinclair1,,
1 Department of Pathology and Glenn Labs for Aging Research, Harvard Medical School, Boston, MA 02115, USA
2 Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
3 University of Wisconsin, Department of Genetics and Medical Genetics, Madison, WI 53706, USA
4 Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
5 The Jackson Laboratory, Bar Harbor, ME 04609, USA
6 Howard Hughes Medical Institute, The Children's Hospital, Immune Disease Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
7 Present address: Max Planck Institute for Experimental Medicine, 37075 G?ttingen, Germany
Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.
