DNA damage tolerance: a double-edged sword guarding the genome.
DNA damage tolerance: a double-edged sword guarding the genome.
复制标题
DOI：
10.3978/j.issn.2218-676x.2013.04.01
复制
发表时间：
2013
影响因子：
0.9
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Ghosal G;Chen J
保持基因组的完整性是细胞稳态的一个重要过程。在单个细胞的生命过程中，基因组不断受到内源性和外源性因子的破坏。为了确保基因组的稳定性，细胞使用一个全球信号网络，即DNA损伤反应（DDR）来感知和修复DNA损伤。DDR感测不同类型的DNA损伤并协调包括转录激活、细胞周期控制、DNA修复途径、凋亡、衰老和细胞死亡的响应。尽管有几种修复机制可以修复不同类型的DNA损伤，但复制机制可能仍然会遇到错误修复或未修复的损伤。受损基因组的复制会导致高频率的叉崩溃和基因组不稳定。在这种情况下，细胞采用DNA损伤耐受（DDT）途径，该途径招募专门的低保真度跨损伤合成（TLS）聚合酶来绕过损伤，以便在稍后的时间点进行修复。因此，DDT本身不是修复途径，但提供了一种在复制期间耐受DNA损伤的机制，从而增加存活率并防止基因组不稳定性。巧合的是，DDT过程也与增加的诱变有关，这反过来又会驱使细胞发展成癌症。因此，DDT过程是一把双刃剑，保护着基因组。本文就复制应激诱导的DNA损伤信号级联反应、DDT途径对停滞复制叉的稳定和拯救以及DDT途径对肿瘤的影响进行综述。
Preservation of genome integrity is an essential process for cell homeostasis. During the course of life of a single cell, the genome is constantly damaged by endogenous and exogenous agents. To ensure genome stability, cells use a global signaling network, namely the DNA damage response (DDR) to sense and repair DNA damage. DDR senses different types of DNA damage and coordinates a response that includes activation of transcription, cell cycle control, DNA repair pathways, apoptosis, senescence, and cell death. Despite several repair mechanisms that repair different types of DNA lesions, it is likely that the replication machinery would still encounter lesions that are mis-repaired or not repaired. Replication of damaged genome would result in high frequency of fork collapse and genome instability. In this scenario, the cells employ the DNA damage tolerance (DDT) pathway that recruits a specialized low fidelity translesion synthesis (TLS) polymerase to bypass the lesions for repair at a later time point. Thus, DDT is not a repair pathway per se, but provides a mechanism to tolerate DNA lesions during replication thereby increasing survival and preventing genome instability. Paradoxically, DDT process is also associated with increased mutagenesis, which can in turn drive the cell to cancer development. Thus, DDT process functions as a double-edged sword guarding the genome. In this review, we will discuss the replication stress induced DNA damage-signaling cascade, the stabilization and rescue of stalled replication forks by the DDT pathway and the effect of the DDT pathway on cancer.