Molecular Basis of Immunoglobulin Heavy Chain Switch

免疫球蛋白重链开关的分子基础

基本信息

批准号：
7846563
负责人：
Janet M. Stavnezer
金额：
$ 2.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-05 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846563
关键词：
Address Affect Alleles Antibodies Antigens B-Lymphocytes Base Excision Repairs Binding CD80 Antigens Chromatin Chromosome Pairing DNA DNA glycosylase DNA-(apurinic or apyrimidinic site) lyase Data Deamination ERCC1 gene Electrophoretic Mobility Shift Assay Enzymes Eukaryota Event Exodeoxyribonuclease I Figs - dietary Genes Genetic Recombination Genetic Transcription Genus Mentha Goals Heavy-Chain Immunoglobulins Homologous Gene IgE Immune response Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin M Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulin Variable Region Induced Mutation Infectious Agent Introns Kinetics Lesion Ligation Mediating Meiosis Mismatch Repair Modeling Molecular Mus Mutate Mutation Nature Nucleotide Excision Repair Pathway interactions Process Protein Binding Proteins Reaction Recruitment Activity Repair Complex Residual state Role Side Single-Stranded DNA Site Specificity Structure Tail Tandem Repeat Sequences Testing Transcript activation-induced cytidine deaminase base constant region gene endonuclease in vivo meetings repair enzyme repaired research study role model uracil-DNA glycosylase variable region gene

Address Affect Alleles Antibodies Antigens B-Lymphocytes Base Excision Repairs Binding CD80 Antigens Chromatin Chromosome Pairing DNA DNA glycosylase DNA-(apurinic or apyrimidinic site) lyase Data Deamination ERCC1 gene Electrophoretic Mobility Shift Assay Enzymes Eukaryota Event Exodeoxyribonuclease I Figs - dietary Genes Genetic Recombination Genetic Transcription Genus Mentha Goals Heavy-Chain Immunoglobulins Homologous Gene IgE Immune response Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin M Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulin Variable Region Induced Mutation Infectious Agent Introns Kinetics Lesion Ligation Mediating Meiosis Mismatch Repair Modeling Molecular Mus Mutate Mutation Nature Nucleotide Excision Repair Pathway interactions Process Protein Binding Proteins Reaction Recruitment Activity Repair Complex Residual state Role Side Single-Stranded DNA Site Specificity Structure Tail Tandem Repeat Sequences Testing Transcript activation-induced cytidine deaminase base constant region gene endonuclease in vivo meetings repair enzyme repaired research study role model uracil-DNA glycosylase variable region gene

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项目摘要

DESCRIPTION (provided by applicant): Upon activation by antigen, B cells undergo antibody class (isotype) switching, changing from expression of IgM to expression of IgG, IgA or IgE, while maintaining specificity for the same antigen. Since the isotype determines the effector function of the antibody, class switching allows the humoral immune response to adaptively respond to different infectious organisms. Class switching occurs by a DMA recombination event between switch (S) region sequences located upstream of each heavy chain constant (CH) region gene. This process has mechanistic similarities to somatic hypermutation of Ig variable region genes. It has recently become clear that activation-induced cytidine deaminase (AID) initiates class switch recombination (CSR) by deamination of dC residues within S regions, creating dU residues. It is thought that single strand (ss) DNA nicks are then created by the base excision repair pathway, which converts dU residues to abasic sites, which are then nicked by AP endonuclease. We hypothesize that mismatch repair (MMR) enzymes recognize U:G mismatches created by AID, recruit Exonuclease 1 to the ss breaks created by base excision repair which excises a ss patch resulting in the conversion of these ss breaks to the double-strand breaks (DSBs) that are required for CSR. We also hypothesize that other mismatches and loops formed at S regions due to collapse of R-loops out-of-register will also recruit MMR proteins to S regions during CSR. There are three specific aims which have the goal of providing evidence for these hypotheses. Aim 1: To determine the roles of the mismatch proteins in CSR. Aim 2: To determine the role of Su tandem repeats and the function of their interaction with MMR proteins. Aim 3: To determine the role of uracil-DNA-glycosylase (UNG) in CSR. In Aim 4, we propose to address the hypothesis that Mlh1 interacts with other mouse MutS homologs during CSR due to our finding that Mlh1 has functions in CSR that are independent of Msh2. Specifically, we propose to investigate whether Msh5 has a role in CSR.

描述（由申请人提供）：抗原激活后，B细胞会经历抗体类（同种型）切换，从IgM的表达转换为IgG，IgA或IgE的表达，同时保持对同一抗原的特异性。由于同种型决定抗体的效应函数，因此类切换允许体液免疫反应适应对不同的感染生物的反应。类开关是通过DMA重组事件在每个重链常数（CH）区域基因上游的开关区域序列之间发生的。该过程与Ig变量区域基因的体细胞超伪标具有机械相似性。最近很明显，激活诱导的胞苷脱氨酶（AID）通过在S区域内的直流残基脱氨基来启动类开关重组（CSR），从而产生DU残基。人们认为然后由基本切除修复途径创建单链（SS）DNA划痕，该途径将DU残基转换为Abasic位点，然后由AP内核酸酶划分。我们假设错配修复（MMR）酶识别由AID产生的U：G不匹配，募集外切核酸酶1至BASE COSCISION REIDION创建的SS断裂，从而使SS贴片造成了SS贴剂，从而导致这些SS断裂转换为CSR所需的双重弹药休息（DSB）。我们还假设在CSR期间，由于R-LOOPS崩溃而形成的其他不匹配和环路也会在S区域形成MMR蛋白。有三个具体目标的目的是为这些假设提供证据。目标1：确定不匹配蛋白在CSR中的作用。目标2：确定串联重复的作用以及它们与MMR蛋白相互作用的功能。目标3：确定尿嘧啶-DNA-糖基酶（UNG）在CSR中的作用。在AIM 4中，我们建议解决MLH1在CSR期间与其他小鼠MUTS相互作用的假设，因为我们发现MLH1在CSR中具有独立于MSH2的功能。具体而言，我们建议研究MSH5是否在CSR中起作用。