衰老是人和動物都無法避免的生理過程,,真核細胞在衰老的過程中基因組會變得失去穩(wěn)定性,,基因表達也會基因組的不穩(wěn)定性而發(fā)生改變。研究發(fā)現(xiàn),,酵母細胞中的組蛋白脫乙?;窼ir2具有沉默轉(zhuǎn)錄子和穩(wěn)定重復DNA的功效,但是,,當細胞開始老化或是DNA斷裂情況發(fā)生的時候,,Sir復合物會失去原來的功能,變得不具有沉默基因的能力,,并最終導致酵母失去自我增殖的能力,,這是酵母老化過程中伴隨發(fā)生的典型特征。
為了解哺乳動物是否具有相似的情況,,研究者用小鼠胚胎干細胞來進行試驗,,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DNA片段各種基因表達的功能,。當DNA發(fā)生斷裂的情況時,,SIRT1就會從基因組轉(zhuǎn)座子上掉落,并重新定位促進DNA修復,,改變轉(zhuǎn)錄過程,,這一情況在老化的細胞中同樣會出現(xiàn)。如果增加SIRT1的表達量可有效保護基因組穩(wěn)定性遭破壞的細胞維持活性,,抑制老化帶來的基因組轉(zhuǎn)錄變化,。
所以說,DNA造到破壞可誘導SIRT1重新分配,并隨之改變基因組的轉(zhuǎn)錄情況,,改變蛋白的表達情況,,這一機制可能是真核細胞在老化過程中一個保守的機制。(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.