DNA double-strand breaks (DSBs) are commonly seen as lesions that threaten genome integrity and contribute to cancer and aging processes. However, in the context of antigen receptor gene assembly, known as V(D)J recombination, DSBs are obligatory intermediates that allow the establishment of genetic diversity and adaptive immunity. V(D)J recombination is initiated when the lymphoid-restricted recombination-activating genes RAG1 and RAG2 are expressed and form a site-specific endonuclease (the RAG nuclease or RAG recombinase). Here, we discuss the ability of the RAG nuclease to minimize the risks of genome disruption by coupling the breakage and repair steps of the V(D)J reaction. This implies that the RAG genes, derived from an ancient transposon, have undergone strong selective pressure to prohibit transposition in favor of promoting controlled DNA end joining in cis by the ubiquitous DNA damage response and DNA repair machineries. We also discuss the idea that, in addition to being essential for the rearrangement of antigen receptor genes, RAG-mediated DSBs could impact cellular processes and outcomes by affecting genetic and epigenetic programs.

中文翻译：

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RAG重组酶：超越断裂。

DNA双链断裂（DSB）通常被视为威胁基因组完整性并导致癌症和衰老过程的病变。但是，在称为V（D）J重组的抗原受体基因组装的背景下，DSB是必不可少的中间体，可以建立遗传多样性和适应性免疫。当淋巴限制的重组激活基因RAG1和RAG2表达并形成位点特异性核酸内切酶（RAG核酸酶或RAG重组酶）时，V（D）J重组开始。在这里，我们讨论了RAG核酸酶通过耦合V（D）J反应的破坏和修复步骤来最大程度地降低基因组破坏风险的能力。这意味着RAG基因源自古代的转座子，由于普遍存在的DNA损伤反应和DNA修复机制，已经经历了强烈的选择性压力来禁止转座，从而促进顺式控制DNA末端连接。我们还讨论了以下想法：除了对抗原受体基因的重排至关重要之外，RAG介导的DSB还可通过影响遗传和表观遗传程序来影响细胞过程和结果。