Université Paris Sud, Laboratoire « Stabilité Génétique et Oncogenèse » CNRS, UMR 8200 and Institut de Cancérologie Gustave-Roussy PR2, 114 Rue Edouard Vaillant, 94805 VILLEJUIF. CNRS, France.
Am J Cancer Res. 2012;2(3):249-68. Epub 2012 Apr 21.
A DNA double strand break (DSB) is a highly toxic lesion, which can generate genetic instability and profound genome rearrangements. However, DSBs are required to generate diversity during physiological processes such as meiosis or the establishment of the immune repertoire. Thus, the precise regulation of a complex network of processes is necessary for the maintenance of genomic stability, allowing genetic diversity but protecting against genetic instability and its consequences on oncogenesis. Two main strategies are employed for DSB repair: homologous recombination (HR) and non-homologous end-joining (NHEJ). HR is initiated by single-stranded DNA (ssDNA) resection and requires sequence homology with an intact partner, while NHEJ requires neither resection at initiation nor a homologous partner. Thus, resection is an pivotal step at DSB repair initiation, driving the choice of the DSB repair pathway employed. However, an alternative end-joining (A-EJ) pathway, which is highly mutagenic, has recently been described; A-EJ is initiated by ssDNA resection but does not require a homologous partner. The choice of the appropriate DSB repair system, for instance according the cell cycle stage, is essential for genome stability maintenance. In this context, controlling the initial events of DSB repair is thus an essential step that may be irreversible, and the wrong decision should lead to dramatic consequences. Here, we first present the main DSB repair mechanisms and then discuss the importance of the choice of the appropriate DSB repair pathway according to the cell cycle phase. In a third section, we present the early steps of DSB repair i.e., DSB signaling, chromatin remodeling, and the regulation of ssDNA resection. In the last part, we discuss the competition between the different DSB repair mechanisms. Finally, we conclude with the importance of the fine tuning of this network for genome stability maintenance and for tumor protection in fine.
双链 DNA 断裂（DSB）是一种高度毒性的损伤，可导致遗传不稳定性和广泛的基因组重排。然而，DSB 是在生理过程中产生多样性所必需的，例如减数分裂或免疫库的建立。因此，精确调节复杂的过程网络对于维持基因组稳定性是必要的，允许遗传多样性，但防止遗传不稳定性及其对肿瘤发生的影响。DSB 修复采用两种主要策略：同源重组（HR）和非同源末端连接（NHEJ）。HR 由单链 DNA（ssDNA）切除引发，需要与完整的伙伴具有序列同源性，而 NHEJ 在起始时不需要切除，也不需要同源伙伴。因此，切除是 DSB 修复起始的关键步骤，决定了所采用的 DSB 修复途径。然而，最近描述了一种替代末端连接（A-EJ）途径，该途径具有高度的突变性；A-EJ 由 ssDNA 切除引发，但不需要同源伙伴。根据细胞周期阶段选择适当的 DSB 修复系统对于维持基因组稳定性至关重要。在这种情况下，控制 DSB 修复的初始事件是一个必不可少的步骤，可能是不可逆的，错误的决策应该会导致严重的后果。在这里，我们首先介绍主要的 DSB 修复机制，然后讨论根据细胞周期阶段选择适当的 DSB 修复途径的重要性。在第三部分，我们介绍 DSB 修复的早期步骤，即 DSB 信号转导、染色质重塑和 ssDNA 切除的调节。在最后一部分，我们讨论了不同 DSB 修复机制之间的竞争。最后，我们得出结论，精细调节这个网络对于维持基因组稳定性和肿瘤保护非常重要。
