HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation.
HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation.
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DOI：
10.1101/gad.349438.122
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发表时间：
2022-04-01
影响因子：
10.5
通讯作者：
Schatz, David G.
中科院分区：
文献类型：
--
作者：
Wu, Lizhen;Shukla, Vipul;Yadavalli, Anurupa Devi;Dinesh, Ravi K.;Xu, Dijin;Rao, Anjana;Schatz, David G.
在此，Wu等人证明DNA修复因子HMCES强烈抑制缺失，而不显著影响小鼠和人B细胞中体细胞超突变的其他参数，从而促进抗原特异性抗体的产生。他们的发现导致了一种新的模型，用于在SHM期间保护IG基因完整性，其中在BER和MMR酶处理脆弱的缺口DNA中间体期间的关键时刻，HMCES的无碱基位点交联被打断。当由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加工时，体细胞超突变（SHM）在B细胞中的免疫球蛋白（IG）基因中产生点突变。这种尿嘧啶加工产生DNA链断裂，并且易于产生有害缺失。在这里，我们证明了DNA修复因子HMCES强烈抑制缺失，而不显着影响其他参数的SHM在小鼠和人B细胞，从而促进抗原特异性抗体的生产。HMCES抑制的缺失倾向性修复途径在尿嘧啶糖基化酶UNG下游发挥作用，并由BER因子APE 2和MMR因子MSH 2、MSH 6和EXO 1的联合作用介导。HMCES在SHM期间屏蔽缺失的能力需要其与脱碱基位点形成共价交联的能力，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复制期间的基因组稳定作用。我们的研究结果导致了一种新的模型，在SHM过程中，在BER和MMR酶处理脆弱的缺口DNA中间体的关键时刻，通过HMCES的脱碱基位点交联的中断保护IG基因的完整性。
Here, Wu et al. demonstrate that the DNA repair factor HMCES strongly suppresses deletions without significantly affecting other parameters of somatic hypermutation in mouse and human B cells, thereby facilitating the production of antigen-specific antibodies. Their 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. 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.
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影响因子：
14.8
作者：
Koch B;Nijmeijer B;Kueblbeck M;Cai Y;Walther N;Ellenberg J
通讯作者：
Ellenberg J
影响因子：
64.5
作者：
Alt FW;Zhang Y;Meng FL;Guo C;Schwer B
通讯作者：
Schwer B
影响因子：
8.8
作者：
Kweon, Soo-Mi;Zhu, Bing;Feldman, Douglas E.
通讯作者：
Feldman, Douglas E.
B细胞中的突变，Kataegis和易位：了解有助于混杂活性。
DOI：
10.1038/nri.2016.2
发表时间：
2016-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Casellas R;Basu U;Yewdell WT;Chaudhuri J;Robbiani DF;Di Noia JM
通讯作者：
Di Noia JM
影响因子：
64.8
作者：
Liu, Man;Duke, Jamie L.;Schatz, David G.
通讯作者：
Schatz, David G.