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HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation
Genes & Development ( IF 7.5 ) Pub Date : 2022-04-01 , DOI: 10.1101/gad.349438.122
Lizhen Wu 1 , Vipul Shukla 2 , Anurupa Devi Yadavalli 1 , Ravi K Dinesh 1 , Dijin Xu 3 , Anjana Rao 2, 4, 5 , David G Schatz 1
Affiliation  

Somatic hypermutation (SHM) produces point mutations in immunoglobulin (Ig) genes in B cells when uracils created by the activation-induced deaminase are processed in a mutagenic manner by enzymes of the base excision repair (BER) and mismatch repair (MMR) pathways. Such uracil processing creates DNA strand breaks and is susceptible to the generation of deleterious deletions. Here, we demonstrate that the DNA repair factor HMCES strongly suppresses deletions without significantly affecting other parameters of SHM in mouse and human B cells, thereby facilitating the production of antigen-specific antibodies. The deletion-prone repair pathway suppressed by HMCES operates downstream from the uracil glycosylase UNG and is mediated by the combined action of BER factor APE2 and MMR factors MSH2, MSH6, and EXO1. HMCES's ability to shield against deletions during SHM requires its capacity to form covalent cross-links with abasic sites, in sharp contrast to its DNA end-joining role in class switch recombination but analogous to its genome-stabilizing role during DNA replication. Our findings lead to a novel model for the protection of Ig gene integrity during SHM in which abasic site cross-linking by HMCES intercedes at a critical juncture during processing of vulnerable gapped DNA intermediates by BER and MMR enzymes.

中文翻译:


HMCES 特别保护免疫球蛋白基因免于体细胞超突变期间的缺失



当激活诱导的脱氨酶产生的尿嘧啶被碱基切除修复 (BER) 和错配修复 (MMR) 途径的酶以诱变方式处理时,体细胞超突变 (SHM) 会在 B 细胞中的免疫球蛋白 (Ig) 基因中产生点突变。这种尿嘧啶加工会造成 DNA 链断裂,并且容易产生有害的缺失。在这里,我们证明DNA修复因子HMCES强烈抑制缺失,而不显着影响小鼠和人类B细胞中SHM的其他参数,从而促进抗原特异性抗体的产生。 HMCES 抑制的易缺失修复途径在尿嘧啶糖基化酶 UNG 下游起作用,并由 BER 因子 APE2 和 MMR 因子 MSH2、MSH6 和 EXO1 的联合作用介导。 HMCES 在 SHM 过程中屏蔽缺失的能力需要其能够与脱碱基位点形成共价交联,这与其在类别转换重组中的 DNA 末端连接作用形成鲜明对比,但类似于其在 DNA 复制过程中的基因组稳定作用。我们的研究结果提出了一种在 SHM 过程中保护 Ig 基因完整性的新模型,其中 HMCES 的无碱基位点交联在 BER 和 MMR 酶处理脆弱缺口 DNA 中间体的关键时刻进行调解。
更新日期:2022-04-01
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