早老素导致基因组不稳定的机制

Mechanism of Genomic Instability Induced by Progerin

基因组不稳定(genomic instability)是机体衰老的标志之一,也是儿童早老症(HutchinsonGilford progeria syndrome,HGPS)患者细胞的典型特征。HGPS的发生与早老素(progerin)堆积密切相关,但早老素如何引起基因组不稳定尚缺乏系统性的阐述。基因组的结构稳定与DNA的正确复制、DNA损伤修复、端粒的维持和稳定以及表观遗传学修饰密切相关。本文主要讨论早老素在改变正常核纤层结构的基础上,通过影响相关通路关键蛋白质的水平或者定位,引起细胞内氧化应激增强、DNA复制应激和DNA损伤修复障碍,细胞DNA损伤增多和端粒的加速缩短,并在改变组蛋白甲基化和乙酰化方面导致基因组不稳定的机制。

Genomic instability is one of hallmarks of aging and the typical characteristics of HutchinsonGilford progeria syndrome(HGPS)cells.HGPS is the result of progerin accumulation.However,there is a lack of systematic explanation on how progerin causes genomic instability.The stability of genomic structure is closely related with correct DNA replication,DNA damage repair,telomere maintenance and stability,and histone epigenetic modification.This review mainly discusses the mechanism by which progerin,on the basis of structure aberration of nucleus lamina,causes intracellular oxidative stress,cellular DNA replication stress,DNA damage repair disorder,and increases cell DNA damage,telomere shortening,and dysregulation of histone methylation and acetylation,to induce genome instability by affecting the level or localization of key proteins in related pathways.