Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Eur J Immunol. 2014 Jul;44(7):1913-6. doi: 10.1002/eji.201444813. Epub 2014 Jun 30.
During the immune response, B cells undergo a programed mutagenic cascade to promote increased affinity and expanded antibody function. The two processes, somatic hypermutation (SHM) and class switch recombination (CSR), are initiated by the protein activation-induced deaminase (AID), which converts cytosine to uracil in the immunoglobulin loci. The presence of uracil in DNA promotes DNA mutagenesis though a subset of DNA repair proteins. Two distinct mechanisms have been proposed to control uracil processing. The first is through base removal by uracil DNA glycosylase (UNG), and the second is through detection by the mismatch repair (MMR) complex MSH2/6. In a study published in this issue of European Journal of Immunology, Dingler et al. [Eur. J. Immunol. 2014. 44: 1925-1935] examine uracil processing in B cells in the absence of UNG and SMUG1 glycosylases. Similar to UNG, SMUG1 is an uracil glycosylase which can remove the uracil base. While Smug1(-/-) mice show no clear deficiency in SHM or CSR, Ung(-/-) Smug1(-/-) mice display exacerbated phenotypes, suggesting a back-up role for SMUG1 in antibody diversity. This new information expands the model of uracil processing in B cells and raises several interesting questions about the dynamic relationship between base excision repair and MMR.
在免疫反应过程中，B 细胞经历程序化的诱变级联反应，以促进亲和力的增加和抗体功能的扩展。这两个过程，体细胞高频突变（SHM）和类别转换重组（CSR），是由蛋白激活诱导的脱氨酶（AID）启动的，它将免疫球蛋白基因座中的胞嘧啶转化为尿嘧啶。DNA 中尿嘧啶的存在通过一组 DNA 修复蛋白促进 DNA 突变。已经提出了两种不同的机制来控制尿嘧啶的处理。第一种是通过尿嘧啶 DNA 糖基化酶（UNG）的碱基去除，第二种是通过错配修复（MMR）复合物 MSH2/6 的检测。在本期《欧洲免疫学杂志》上发表的一项研究中，Dingler 等人 [Eur. J. Immunol. 2014. 44: 1925-1935] 研究了 UNG 和 SMUG1 糖苷酶缺失的 B 细胞中的尿嘧啶处理。与 UNG 相似，SMUG1 是一种尿嘧啶糖苷酶，可以去除尿嘧啶碱基。虽然 Smug1(-/-) 小鼠在 SHM 或 CSR 中没有明显的缺陷，但 Ung(-/-) Smug1(-/-) 小鼠显示出加重的表型，这表明 SMUG1 在抗体多样性中具有备用作用。这一新信息扩展了 B 细胞中尿嘧啶处理的模型，并提出了关于碱基切除修复和 MMR 之间动态关系的几个有趣问题。
