National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
J Biol Chem. 2010 Nov 12;285(46):35267-73. doi: 10.1074/jbc.M110.161208. Epub 2010 Aug 20.
B cell maturation and B cell-mediated antibody response require programmed DNA modifications such as the V(D)J recombination, the immunoglobulin (Ig) class switch recombination, and the somatic hypermutation to generate functional Igs. Many protein factors involved in DNA damage repair have been shown to be critical for the maturation and activation of B cells. Rad9 plays an important role in both DNA repair and cell cycle checkpoint control. However, its role in Ig generation has not been reported. In this study, we generated a conditional knock-out mouse line in which Rad9 is deleted specifically in B cells and investigated the function of Rad9 in B cells. The Rad9(-/-) B cells isolated from the conditional knock-out mice displayed impaired growth response and enhanced DNA lesions. Impaired Ig production in response to immunization in Rad9(-/-) mice was also detected. In addition, the Ig class switch recombination is deficient in Rad9(-/-) B cells. Taken together, Rad9 plays dual roles in generating functional antibodies and in maintaining the integrity of the whole genome in B cells.
B 细胞成熟和 B 细胞介导的抗体反应需要程序性 DNA 修饰，如 V(D)J 重组、免疫球蛋白（Ig）类别转换重组和体细胞超突变，以产生功能性 Ig。许多参与 DNA 损伤修复的蛋白质因子已被证明对 B 细胞的成熟和激活至关重要。Rad9 在 DNA 修复和细胞周期检查点控制中都发挥着重要作用。然而，其在 Ig 产生中的作用尚未得到报道。在本研究中，我们生成了一种条件性敲除小鼠品系，其中 Rad9 特异性缺失于 B 细胞中，并研究了 Rad9 在 B 细胞中的功能。从条件性敲除小鼠中分离的 Rad9(-/-) B 细胞显示出生长反应受损和 DNA 损伤增强。在 Rad9(-/-)小鼠中，针对免疫接种的 Ig 产生也受到损害。此外，Rad9(-/-) B 细胞中的 Ig 类别转换重组缺陷。总之，Rad9 在产生功能性抗体和维持 B 细胞整个基因组完整性方面发挥双重作用。
