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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：
8639438
负责人：
CAROL E SCHRADER
金额：
$ 45.43万
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：
1985
资助国家：
美国
起止时间：
1985-08-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8639438
关键词：
APEX1 gene Address Affect Antibodies B-Cell Lymphomas B-Lymphocytes Bacterial Toxins Base Excision Repairs Binding Cell Cycle Cells Chromosomal Breaks Chromosomal translocation Chromosomes Complex DNA DNA Double Strand Break DNA Repair Gene DNA Repair Pathway DNA Single Strand Break DNA biosynthesis DNA repair protein DNA-(apurinic or apyrimidinic site) lyase Deamination Dependence Enhancers Enzyme Activation Event Frequencies G1 Phase Genes Genetic Recombination Genome Grant Heavy-Chain Immunoglobulins Human IGH@ gene cluster IgE Immune response Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Genes Immunoglobulin Isotypes Immunoglobulin M Immunoglobulin Switch Recombination Immunoglobulins Lead Lesion Ligation Light MYC gene Malignant Neoplasms Maps Mature B-Lymphocyte Mediating Methods Microsatellite Instability Mismatch Repair Modeling Molecular Mus Mutation Oncogene Activation Oncogenes Pathway interactions Plasmacytoma Positioning Attribute Process Proteins Publishing Recruitment Activity Relative (related person)Reporting Role Site Structure of germinal center of lymph node System Time activation-induced cytidine deaminase base c-myc Genes chromatin immunoprecipitation follow-up genome-wide improved metaplastic cell transformation pathogen prevent public health relevance repair enzyme repaired research study uracil-DNA glycosylase

项目摘要

DESCRIPTION (provided by applicant): Antibody (immunoglobulin, Ig) class switch causes B lymphocytes to switch from producing IgM to producing IgG, IgA or IgE, which improves the ability of the antibody to remove pathogens and bacterial toxins from the body. Class switching occurs by an intrachromosomal DNA recombination event that must be carefully controlled in order to avoid aberrant recombination with other chromosomes (translocations). However, translocations do occur between oncogenes and the IgH locus, and this can lead to B cell lymphomas. During class switching, activation-induced cytidine deaminase (AID) initiates the formation of DNA double strand breaks (DSBs) at switch (S) regions in the Ig heavy chain gene locus (IgH), which are necessary for class switching. My first Aim is to determine how deamination of dC's in Ig S regions by AID, forming dU's, results in DSBs. We have shown that AID-induced deamination of dC leads to DNA single-strand breaks (SSBs) via the base excision repair pathway. How these SSBs are then converted to DSBs is less clear. We have reported that another DNA repair pathway, mismatch repair (MMR) is important for this step, and we will investigate its role. We will investigate how SSBs are converted to DSBs by determining the frequency and sites of AID- induced dU's in S regions, how the frequency and positions of AID targets affects frequency of switching, and whether MMR proteins might be recruited to S regions by AID itself. In Aim 2 we will follow up on our finding during the current term of this grant that AID can instigate DSBs at sites other than the IgH locus in activated B cells. We will determine what makes these other sites targets for AID, and if these DSBs lead to chromosome breaks, deletions and translocations, and whether MMR and other DNA repair proteins known to be involved in CSR, for example, ATM, H2AX, and 53BP1 are involved in making or preventing these DSBs.

描述（申请人提供）：抗体（免疫球蛋白，Ig）类别转换导致B淋巴细胞从产生IgM转变为产生IgG、IgA或IgE，从而提高抗体清除体内病原体和细菌毒素的能力。类别转换是通过染色体内 DNA 重组事件发生的，必须仔细控制该重组事件，以避免与其他染色体发生异常重组（易位）。然而，癌基因和 IgH 基因座之间确实会发生易位，这可能导致 B 细胞淋巴瘤。在类别转换期间，激活诱导的胞苷脱氨酶 (AID) 会在 Ig 重链基因座 (IgH) 的转换 (S) 区域启动 DNA 双链断裂 (DSB) 的形成，这是类别转换所必需的。我的第一个目标是确定 AID 如何使 Ig S 区域中的 dC 脱氨，形成 dU，从而产生 DSB。我们已经证明，AID 诱导的 dC 脱氨基作用通过碱基切除修复途径导致 DNA 单链断裂 (SSB)。这些 SSB 如何转换为 DSB 尚不清楚。我们已经报道了另一种 DNA 修复途径，错配修复 (MMR) 对于这一步很重要，我们将研究它的作用。我们将通过确定 S 区中 AID 诱导的 dU 的频率和位点来研究 SSB 如何转换为 DSB，AID 靶标的频率和位置如何影响转换频率，以及 AID 本身是否可能将 MMR 蛋白招募到 S 区。在目标 2 中，我们将在本次资助的当前期限内跟进我们的发现，即 AID 可以在激活的 B 细胞中 IgH 基因座以外的位点激发 DSB。我们将确定是什么使这些其他位点成为 AID 的靶点，这些 DSB 是否会导致染色体断裂、缺失和易位，以及 MMR 和已知参与 CSR 的其他 DNA 修复蛋白（例如 ATM、H2AX 和 53BP1）是否参与产生或阻止这些 DSB。

项目成果

期刊论文数量（63）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions.

DOI：
10.1084/jem.20011877
发表时间：
2002-02-04
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Schrader CE;Vardo J;Stavnezer J
通讯作者：
Stavnezer J

Inhibitors of poly(ADP-ribose) polymerase increase antibody class switching.

聚（ADP-核糖）聚合酶抑制剂可增加抗体类别转换。

DOI：
发表时间：
1993
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Shockett,P;Stavnezer,J
通讯作者：
Stavnezer,J

A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination.

DNA 断裂和磷酸化依赖性正反馈环路促进免疫球蛋白类别转换重组。

DOI：
10.1038/ni.2732
发表时间：
2013
期刊：
Nature immunology
影响因子：
30.5
作者：
Vuong,BaoQ;Herrick-Reynolds,Kayleigh;Vaidyanathan,Bharat;Pucella,JosephN;Ucher,AnnaJ;Donghia,NinaM;Gu,Xiwen;Nicolas,Laura;Nowak,Urszula;Rahman,Numa;Strout,MatthewP;Mills,KevinD;Stavnezer,Janet;Chaudhuri,Jayanta
通讯作者：
Chaudhuri,Jayanta

Mouse antibody response to group A streptococcal carbohydrate.

小鼠抗体对 A 组链球菌碳水化合物的反应。