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HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-15 , DOI: 10.1016/j.molcel.2019.10.031 Vipul Shukla 1 , Levon Halabelian 2 , Sanjana Balagere 1 , Daniela Samaniego-Castruita 1 , Douglas E Feldman 3 , Cheryl H Arrowsmith 4 , Anjana Rao 5 , L Aravind 6
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-15 , DOI: 10.1016/j.molcel.2019.10.031 Vipul Shukla 1 , Levon Halabelian 2 , Sanjana Balagere 1 , Daniela Samaniego-Castruita 1 , Douglas E Feldman 3 , Cheryl H Arrowsmith 4 , Anjana Rao 5 , L Aravind 6
Affiliation
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HMCES (5hmC binding, embryonic stem cell-specific-protein), originally identified as a protein capable of binding 5-hydroxymethylcytosine (5hmC), an epigenetic modification generated by TET proteins, was previously reported to covalently crosslink to DNA at abasic sites via a conserved cysteine. We show here that Hmces-deficient mice display normal hematopoiesis without global alterations in 5hmC. HMCES specifically enables DNA double-strand break repair through the microhomology-mediated alternative-end-joining (Alt-EJ) pathway during class switch recombination (CSR) in B cells, and HMCES deficiency leads to a significant defect in CSR. HMCES mediates Alt-EJ through its SOS-response-associated-peptidase domain (SRAPd), a function that requires DNA binding but is independent of its autopeptidase and DNA-crosslinking activities. We show that HMCES is recruited to switch regions of the immunoglobulin locus and provide a potential structural basis for the interaction of HMCES with long DNA overhangs generated by Alt-EJ during CSR. Our studies provide further evidence for a specialized role for HMCES in DNA repair.
中文翻译：
HMCES在B细胞类开关重组过程中在DNA DSB修复的另一种末端连接途径中发挥作用。
HMCES（5hmC结合，胚胎干细胞特异性蛋白）最初被鉴定为能够结合TET蛋白产生的表观遗传修饰的5-羟甲基胞嘧啶（5hmC）的蛋白，以前曾报道它通过脱氧核糖核酸在无碱基位点与DNA共价交联。保守的半胱氨酸。我们在这里显示，Hmces缺陷小鼠显示正常的造血功能，而在5hmC中没有全局改变。HMCES在B细胞中的类开关重组（CSR）期间，通过微同源介导的交替末端连接（Alt-EJ）途径，特别能够实现DNA双链断裂修复，而HMCES缺失会导致CSR的重大缺陷。HMCES通过其SOS反应相关肽酶结构域（SRAPd）介导Alt-EJ，该功能需要DNA结合，但不依赖其自身肽酶和DNA交联活性。我们显示，HMCES被招募来切换免疫球蛋白基因座的区域，并为CCES期间HMCES与Alt-EJ产生的长DNA突出端相互作用提供了潜在的结构基础。我们的研究为HMCES在DNA修复中的特殊作用提供了进一步的证据。
更新日期：2019-12-02
中文翻译：
HMCES在B细胞类开关重组过程中在DNA DSB修复的另一种末端连接途径中发挥作用。
HMCES（5hmC结合，胚胎干细胞特异性蛋白）最初被鉴定为能够结合TET蛋白产生的表观遗传修饰的5-羟甲基胞嘧啶（5hmC）的蛋白，以前曾报道它通过脱氧核糖核酸在无碱基位点与DNA共价交联。保守的半胱氨酸。我们在这里显示，Hmces缺陷小鼠显示正常的造血功能，而在5hmC中没有全局改变。HMCES在B细胞中的类开关重组（CSR）期间，通过微同源介导的交替末端连接（Alt-EJ）途径，特别能够实现DNA双链断裂修复，而HMCES缺失会导致CSR的重大缺陷。HMCES通过其SOS反应相关肽酶结构域（SRAPd）介导Alt-EJ，该功能需要DNA结合，但不依赖其自身肽酶和DNA交联活性。我们显示，HMCES被招募来切换免疫球蛋白基因座的区域，并为CCES期间HMCES与Alt-EJ产生的长DNA突出端相互作用提供了潜在的结构基础。我们的研究为HMCES在DNA修复中的特殊作用提供了进一步的证据。
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