DNA损伤检验点与损伤修复及基因组稳定性

生物有机体基因组DNA经常会受到内源或外源因素的影响而导致结构发生变化，产生损伤；在长期进化过程中，有机体也相应形成了一系列应对与修复损伤DNA，并维持染色体基因组正常结构功能的机制。其中DNA损伤检验点（DNA damage checkpoint）就是在感应DNA损伤的基础上，对损伤感应信号进行转导，或引起细胞周期的暂停，从而使细胞有足够的时间对损伤DNA进行修复，或最终导致细胞发生凋亡。DNA损伤检验点信号转导途径是一个高度保守的信号感应过程，整个途径大致可以分为损伤感应、信号传递及信号效应3个组成部分。其中3-磷脂酰肌醇激酶家族类成员ATM（ataxia-telangiectasia mutated）和ATR（ataxia-telangiectasia and Rad3-related）活性的增加构成整个途径活化的第一步。它们通过激活下游的效应激酶，Chk2／Chk1，通过协同作用许多其他调控细胞周期、DNA复制、DNA损伤修复及细胞凋亡等过程的蛋白质因子来实现细胞对DNA损伤的高度协调反应。近十几年，随着此领域研究的不断深入，人们逐步揭示了DNA损伤检验点途径发生过程中，各种核心组分通过与不同调节因子、效应因子及DNA损伤修复蛋白间的复杂相互作用，以实现监测感应异常DNA结构并实施相应反应的机制；其中，检验点衔接因子（mediators）及染色质结构，尤其是核小体组蛋白的共价修饰在调控ATM／ATR活性，促进ATM／ATR与底物间的相互作用以及介导DNA损伤位点周围染色质区域上多蛋白复合物在时间与空间上的动态形成发挥着重要的作用。同时，人们也开始发现DNA损伤检验点途径与DNA损伤修复、基因组稳定性以及肿瘤发生等过程之间某些内在的联系。该反应途径在通过协调细胞针对DNA损伤做出各种反应的基础上，直接或间接地参与或调控DNA损伤修复过程，并与DNA损伤修复途径协同作用最终保证染色体基凶组结构的完整性，而检验点途径的改变，则会引起基因组不稳定的发生，包括从突变频率的提高到大范围的染色体重排，以及染色体数量的畸变。如：突变发生在肿瘤形成早期，会大大增加肿瘤发生的几率。文章将对DNA损伤检验点途径机制及其对DNA损伤修复、基因组稳定性影响的最新进展进行综述。

DNA Damage Checkpoint, Damage Repair, and Genome Stability

Genomic DNA is under constant attack from both endogenous and exogenous sources of DNA damaging agents. Without proper care, the ensuing DNA damages would lead to alteration of genomic structure thus affecting the faithful transmission of genetic information, During the process of evolution, organisms have acquired a series of mechanisms responding to and repairing DNA damage, thus assuring the maintenance of genome stability and faithful transmission of genetic information. DNA damage checkpoint is one such important mechanism by which, in the face of DNA damage, a cell can respond to amplified damage signals, either by actively halting the cell cycle until it ensures that critical processes such as DNA replication or mitosis are complete or by initiating apoptosis as a last resort, Over the last decade, complex hierarchical interactions between the key components like ATM/ATR in the checkpoint pathway and various other mediators, effectors including DNA damage repair proteins have begun to emerge. In the meantime, an intimate relationship between mechanisms of damage checkpoint pathway, DNA damage repair, and genome stability was also uncovered. Reviewed hereinare the recent findings on both the mechanisms of activation of checkpoint pathways and their coordination with DNA damage repair machinery as well as their effect on genomic integrity.