NBS1在V(D)J重组中间体的替代性非同源末端连接中的作用。
Roles for NBS1 in alternative nonhomologous end-joining of V(D)J recombination intermediates.
作者信息
Deriano Ludovic, Stracker Travis H, Baker Annalee, Petrini John H J, Roth David B
机构信息
Department of Pathology, The Helen L and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine and , New York University School of Medicine, New York, NY 10016, USA.
出版信息
Mol Cell. 2009 Apr 10;34(1):13-25. doi: 10.1016/j.molcel.2009.03.009.
Recent work has highlighted the importance of alternative, error-prone mechanisms for joining DNA double-strand breaks (DSBs) in mammalian cells. These noncanonical, nonhomologous end-joining (NHEJ) pathways threaten genomic stability but remain poorly characterized. The RAG postcleavage complex normally prevents V(D)J recombination-associated DSBs from accessing alternative NHEJ. Because the MRE11/RAD50/NBS1 complex localizes to RAG-mediated DSBs and possesses DNA end tethering, processing, and joining activities, we asked whether it plays a role in the mechanism of alternative NHEJ or participates in regulating access of DSBs to alternative repair pathways. We find that NBS1 is required for alternative NHEJ of hairpin coding ends, suppresses alternative NHEJ of signal ends, and promotes proper resolution of inversional recombination intermediates. These data demonstrate that the MRE11 complex functions at two distinct levels, regulating repair pathway choice (likely through enhancing the stability of DNA end complexes) and participating in alternative NHEJ of coding ends.
最近的研究突出了哺乳动物细胞中用于连接DNA双链断裂（DSB）的替代性、易出错机制的重要性。这些非经典的非同源末端连接（NHEJ）途径威胁基因组稳定性，但目前仍了解甚少。RAG切割后复合物通常会阻止V（D）J重组相关的DSB进入替代性NHEJ。由于MRE11/RAD50/NBS1复合物定位于RAG介导的DSB，并具有DNA末端拴系、加工和连接活性，我们探究它是否在替代性NHEJ机制中发挥作用，或参与调控DSB进入替代性修复途径。我们发现，NBS1是发夹编码末端替代性NHEJ所必需的，可抑制信号末端的替代性NHEJ，并促进倒位重组中间体的正确拆分。这些数据表明，MRE11复合物在两个不同层面发挥作用，调控修复途径的选择（可能是通过增强DNA末端复合物的稳定性），并参与编码末端的替代性NHEJ。
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