Gorospe Myriam, de Cabo Rafael
Laboratory of Cellular and Molecular Biology, National Institute on Aging - Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Trends Cell Biol. 2008 Feb;18(2):77-83. doi: 10.1016/j.tcb.2007.11.007. Epub 2008 Jan 22.
In mammalian cells, changes in signaling networks and expressed proteins ensure the adequate detection and management of damaged macromolecules. Here, we review an emergent pathway of maintenance of homeostasis following genotoxic stress. The RNA-binding protein HuR associates with sirtuin (SIRT)1 mRNA and maintains constitutively elevated levels of SIRT1 protein, a deacetylase that elicits a prosurvival function. SIRT1 was recently shown to deacetylate the Nijmegen breakage syndrome (NBS1) protein, thereby rendering it phosphorylatable by ataxia telangiectasia mutated protein (ATM). A component of the MRN (MRE11-RAD50-NBS1) nuclease complex, NBS1 is crucial for sensing DNA damage and mounting a genotoxic response. This article covers the regulatory pathway of HuR-->SIRT1-->NBS1, through which post-transcriptional and post-translational effectors contribute to the maintenance of genomic integrity.
在哺乳动物细胞中,信号网络和表达蛋白的变化确保了对受损大分子的充分检测和管理。在此,我们综述了基因毒性应激后维持体内平衡的一条新出现的途径。RNA结合蛋白HuR与沉默调节蛋白(SIRT)1 mRNA结合,并维持SIRT1蛋白的持续高水平,SIRT1是一种具有促生存功能的脱乙酰酶。最近研究表明,SIRT1使尼曼-匹克氏病(NBS1)蛋白脱乙酰化,从而使其可被共济失调毛细血管扩张症突变蛋白(ATM)磷酸化。NBS1是MRN(MRE11-RAD50-NBS1)核酸酶复合体的一个组成部分,对感知DNA损伤并引发基因毒性反应至关重要。本文涵盖了HuR→SIRT1→NBS1的调控途径,通过该途径,转录后和翻译后效应器有助于维持基因组完整性。