Department of Biochemistry and Molecular Biology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614-0581, USA.
Biochem Soc Trans. 2011 Dec;39(6):1764-9. doi: 10.1042/BST20110687.
A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson-Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression.
早衰综合征的一个共同特征是过早衰老表型和修复系统受损导致的 DNA 损伤积累增加。HGPS（Hutchinson-Gilford 早衰综合征）是一种严重的早衰形式，患者体内积累了源自 lamin A/C 基因突变剪接体的突变 lamin A 蛋白（LMNA），即 progerin。Progerin 导致染色质紊乱，进而导致双链断裂（DSBs）和异常 DDR（DNA 损伤反应）的形成。在本文中，我们回顾了最近的研究结果，这些结果解决了 progerin 如何在 HGPS 细胞中破坏 DDR 途径的一些机制细节。我们提出，progerin 的积累导致一些复制和修复因子的功能紊乱，导致 XPA（着色性干皮病组 A）蛋白错误定位到复制叉，复制叉停滞，随后导致 DNA DSBs。XPA 与停滞的叉结合排除了修复蛋白的正常结合，导致 DSB 积累，从而激活 ATM（共济失调毛细血管扩张突变）和 ATR（ATR 相关）检查点，并阻止细胞周期进程。
