Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Genetics, Harvard Medical School, Boston, MA 02115, United States.
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Genetics, Harvard Medical School, Boston, MA 02115, United States.
DNA Repair (Amst). 2014 May;17:52-63. doi: 10.1016/j.dnarep.2014.04.004. Epub 2014 Apr 24.
Developing B and T lymphocytes generate programmed DNA double strand breaks (DSBs) during the V(D)J recombination process that assembles exons that encode the antigen-binding variable regions of antibodies. In addition, mature B lymphocytes generate programmed DSBs during the immunoglobulin heavy chain (IgH) class switch recombination (CSR) process that allows expression of different antibody heavy chain constant regions that provide different effector functions. During both V(D)J recombination and CSR, DSB intermediates are sensed by the ATM-dependent DSB response (DSBR) pathway, which also contributes to their joining via classical non-homologous end-joining (C-NHEJ). The precise nature of the interplay between the DSBR and C-NHEJ pathways in the context of DSB repair via C-NHEJ remains under investigation. Recent studies have shown that the XLF C-NHEJ factor has functional redundancy with several members of the ATM-dependent DSBR pathway in C-NHEJ, highlighting unappreciated major roles for both XLF as well as the DSBR in V(D)J recombination, CSR and C-NHEJ in general. In this review, we discuss current knowledge of the mechanisms that contribute to the repair of DSBs generated during B lymphocyte development and activation with a focus on potential functionally redundant roles of XLF and ATM-dependent DSBR factors.
在 V(D)J 重组过程中，B 和 T 淋巴细胞会产生程序性 DNA 双链断裂（DSB），从而组装编码抗体抗原结合可变区的外显子。此外，成熟 B 淋巴细胞在免疫球蛋白重链（IgH）类别转换重组（CSR）过程中会产生程序性 DSB，从而允许表达不同的抗体重链恒定区，提供不同的效应功能。在 V(D)J 重组和 CSR 过程中，ATM 依赖性 DSB 反应（DSBR）途径会感知 DSB 中间产物，该途径也有助于通过经典非同源末端连接（C-NHEJ）进行连接。在通过 C-NHEJ 进行 DSB 修复的情况下，DSBR 和 C-NHEJ 途径之间的确切相互作用性质仍在研究中。最近的研究表明，XLF C-NHEJ 因子在 C-NHEJ 中与 ATM 依赖性 DSBR 途径的几个成员具有功能冗余性，这突显了 XLF 以及 DSBR 在 V(D)J 重组、CSR 和 C-NHEJ 中的作用被严重低估。在这篇综述中，我们讨论了有助于修复 B 淋巴细胞发育和激活过程中产生的 DSB 的机制的现有知识，重点介绍了 XLF 和 ATM 依赖性 DSBR 因子在功能上可能存在冗余的作用。
