Jeggo Penny A, Löbrich Markus
Genome Damage and Stability Centre, University of Sussex, East Sussex BN1 9RQ, UK.
DNA Repair (Amst). 2006 Sep 8;5(9-10):1192-8. doi: 10.1016/j.dnarep.2006.05.011. Epub 2006 Jun 21.
DNA damage response mechanisms encompass pathways of DNA repair, cell cycle checkpoint arrest and apoptosis. Together, these mechanisms function to maintain genomic stability in the face of exogenous and endogenous DNA damage. ATM is activated in response to double strand breaks and initiates cell cycle checkpoint arrest. Recent studies in human fibroblasts have shown that ATM also regulates a mechanism of end-processing that is required for a component of double strand break repair. Human fibroblasts rarely undergo apoptosis after ionising radiation and, therefore, apoptosis is not considered in our review. The dual function of ATM raises the question as to how the two processes, DNA repair and checkpoint arrest, interplay to maintain genomic stability. In this review, we consider the impact of ATM's repair and checkpoint functions to the maintenance of genomic stability following irradiation in G2. We discuss evidence that ATM's repair function plays little role in the maintenance of genomic stability following exposure to ionising radiation. ATM's checkpoint function has a bigger impact on genomic stability but strikingly the two damage response pathways co-operate in a more than additive manner. In contrast, ATM's repair function is important for survival post irradiation.
DNA损伤反应机制包括DNA修复、细胞周期检查点停滞和凋亡途径。这些机制共同作用，在面对外源性和内源性DNA损伤时维持基因组稳定性。ATM在双链断裂时被激活，并启动细胞周期检查点停滞。最近对人类成纤维细胞的研究表明，ATM还调节双链断裂修复的一个组成部分所需的末端加工机制。人类成纤维细胞在电离辐射后很少发生凋亡，因此，我们的综述中不考虑凋亡。ATM的双重功能引发了一个问题，即DNA修复和检查点停滞这两个过程如何相互作用以维持基因组稳定性。在本综述中，我们考虑了ATM的修复和检查点功能对G2期照射后基因组稳定性维持的影响。我们讨论了证据，表明ATM的修复功能在暴露于电离辐射后对基因组稳定性的维持作用不大。ATM的检查点功能对基因组稳定性有更大的影响，但引人注目的是，这两个损伤反应途径以超加性方式协同作用。相比之下,ATM的修复功能对辐射后的存活很重要。
