Centre National de la Recherche Scientifique UMR8200, Gustave Roussy, 94805, Villejuif, France.
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Sci Rep. 2020 Jan 28;10(1):1311. doi: 10.1038/s41598-020-58180-7.
Somatic hypermutation of immunoglobulin genes is a highly mutagenic process that is B cell-specific and occurs during antigen-driven responses leading to antigen specificity and antibody affinity maturation. Mutations at the Ig locus are initiated by Activation-Induced cytidine Deaminase and are equally distributed at G/C and A/T bases. This requires the establishment of error-prone repair pathways involving the activity of several low fidelity DNA polymerases. In the physiological context, the G/C base pair mutations involve multiple error-prone DNA polymerases, while the generation of mutations at A/T base pairs depends exclusively on the activity of DNA polymerase η. Using two large cohorts of individuals with xeroderma pigmentosum variant (XP-V), we report that the pattern of mutations at Ig genes becomes highly enriched with large deletions. This observation is more striking for patients older than 50 years. We propose that the absence of Pol η allows the recruitment of other DNA polymerases that profoundly affect the Ig genomic landscape.
体细胞高频突变是一种高度突变的过程，它是 B 细胞特异性的，发生在抗原驱动的反应中，导致抗原特异性和抗体亲和力成熟。Ig 基因座上的突变是由激活诱导的胞嘧啶脱氨酶引发的，在 G/C 和 A/T 碱基上均匀分布。这需要建立易错修复途径，涉及几种低保真度 DNA 聚合酶的活性。在生理环境中，G/C 碱基对的突变涉及多种易错 DNA 聚合酶，而 A/T 碱基对的突变则完全依赖于 DNA 聚合酶 η 的活性。我们使用两个大的 XP-V 变异型着色性干皮病个体队列，报告称 Ig 基因的突变模式变得高度富含大片段缺失。这一观察结果在年龄大于 50 岁的患者中更为明显。我们提出，Pol η 的缺失允许其他 DNA 聚合酶的募集，这些聚合酶会深刻影响 Ig 基因组景观。
