School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
Front Immunol. 2019 Jul 4;10:1572. doi: 10.3389/fimmu.2019.01572. eCollection 2019.
V(D)J recombination generates antigen receptor diversity by mixing and matching individual variable (V), diversity (D), and joining (J) gene segments. An obligate by-product of many of these reactions is the excised signal circle (ESC), generated by excision of the DNA from between the gene segments. Initially, the ESC was believed to be inert and formed to protect the genome from reactive broken DNA ends but more recent work suggests that the ESC poses a substantial threat to genome stability. Crucially, the recombinase re-binds to the ESC, which can result in it being re-integrated back into the genome, to cause potentially oncogenic insertion events. In addition, very recently, the ESC/recombinase complex was found to catalyze breaks at recombination signal sequences (RSSs) throughout the genome, via a "cut-and-run" mechanism. Remarkably, the ESC/recombinase complex triggers these breaks at key leukemia driver genes, implying that this reaction could be a significant cause of lymphocyte genome instability. Here, we explore these alternate pathways and discuss their relative dangers to lymphocyte genome stability.
V(D)J 重组通过混合和匹配个体可变 (V)、多样性 (D) 和连接 (J) 基因片段来产生抗原受体多样性。这些反应中的许多强制性副产物是从基因片段之间的 DNA 切除产生的切除信号环 (ESC)。最初，认为 ESC 是惰性的，形成是为了保护基因组免受反应性断裂 DNA 末端的影响，但最近的研究表明，ESC 对基因组稳定性构成重大威胁。至关重要的是，重组酶重新结合到 ESC，这可能导致其重新整合到基因组中，从而导致潜在的致癌插入事件。此外，最近还发现 ESC/重组酶复合物通过“切和跑”机制在整个基因组中的重组信号序列 (RSS) 处催化断裂。值得注意的是，ESC/重组酶复合物在关键白血病驱动基因处触发这些断裂，这意味着该反应可能是淋巴细胞基因组不稳定性的一个重要原因。在这里，我们探讨了这些替代途径，并讨论了它们对淋巴细胞基因组稳定性的相对危险。
