Mechanistic Elucidation of Class Switch Recombination and Somatic Hypermutation

类别转换重组和体细胞超突变的机制阐明

基本信息

批准号：
10230368
负责人：
Jayanta Chaudhuri
金额：
$ 53.1万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2009-07-01 至 2021-02-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10230368
关键词：
ATP phosphohydrolase ATPase Domain Address Affinity Amino Acids Activation Antigens B-Cell Lymphomas B-Lymphocytes Base Excision Repairs Binding CHD4 gene Cell Death Cells Cellular Immunity Chromatin Chromosomal translocation DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Sequence Alteration Data Deamination Deoxycytidine Deoxyuridine Double Strand Break Repair Exons Failure Fibroblasts Funding Generations Genes Genetic Recombination Genomics Goals Growth Heavy-Chain Immunoglobulins Human IgE Immune response Immunity Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin Constant Region Immunoglobulin G Immunoglobulin Genes Immunoglobulin M Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulin Variable Region Immunologic Deficiency Syndromes Impairment Individual Knock-in Knock-in Mouse Knowledge Lead Lesion Lymphoma Mature B-Lymphocyte Mediating Mismatch Repair Mus Mutant Strains Mice Mutate Mutation Pathologic Mutagenesis Patients Phase Proteins Publishing Reaction Role Testing Virus Diseases Work activation-induced cytidine deaminase base cancer type density experimental study genome integrity in vivo influenzavirus insight novel overexpression preservation prevent recruit repaired response

项目摘要

ABSTRACT Upon encountering antigens, mature B cells express activation induced cytidine deaminase (AID) and undergo immunoglobulin heavy chain (Igh) class switch recombination (CSR) and somatic hypermutation (SHM). CSR proceeds through the obligate generation of DNA double strand breaks (DSBs), which constitute one of the most toxic lesions that can occur in a cell. A single unrepaired DSB can cause cell death or potentiate chromosomal translocations that are hallmarks of many types of cancer, including lymphomas. Thus, mechanisms that promote generation of DSBs and facilitate DSB repair are intergral to both immunity and preservation of genomic integrity. In this proposal we test the notion that single proteins can coordinate both DSB formation and mediate end-joining to efficiently generate and repair DSBs. We test the hypothesis that the nucleosomal remodeling protein CHD4 co-ordinates generation and repair of Igh DSBs (aim 1) and the C- terminus of AID mediates efficient DNA repair of Igh DSBs (aim 2). Successful completion of the experiments will have far reaching implications in our understanding of both B cell immunity and B cell lymphomas.

抽象的遇到抗原后，成熟 B 细胞表达激活诱导的胞苷脱氨酶 (AID)，并经历免疫球蛋白重链 (Igh) 类转换重组 (CSR) 和体细胞超突变 (SHM)。企业社会责任通过必然产生 DNA 双链断裂 (DSB) 来进行，这构成了 DNA 双链断裂之一细胞中可能发生的大多数毒性损伤。单个未修复的 DSB 可导致细胞死亡或增强染色体易位是许多类型癌症（包括淋巴瘤）的标志。因此，促进 DSB 生成和促进 DSB 修复的机制对于免疫和免疫系统都是不可或缺的。保持基因组完整性。在这个提案中，我们测试了单一蛋白质可以协调两者的概念 DSB 形成和介导末端连接，以有效生成和修复 DSB。我们检验以下假设：核小体重塑蛋白 CHD4 协调 Igh DSB 的生成和修复（目标 1）和 C- AID 末端介导 Igh DSB 的有效 DNA 修复（目标 2）。实验顺利完成将对我们对 B 细胞免疫和 B 细胞淋巴瘤的理解产生深远的影响。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The aryl hydrocarbon receptor controls cell-fate decisions in B cells.

DOI：
10.1084/jem.20160789
发表时间：
2017-01
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Vaidyanathan B;Chaudhry A;Yewdell WT;Angeletti D;Yen WF;Wheatley AK;Bradfield CA;McDermott AB;Yewdell JW;Rudensky AY;Chaudhuri J
通讯作者：
Chaudhuri J

TIRR regulates 53BP1 by masking its histone methyl-lysine binding function.

DOI：
10.1038/nature21358
发表时间：
2017-03-09
期刊：
Nature
影响因子：
64.8
作者：
Drané P;Brault ME;Cui G;Meghani K;Chaubey S;Detappe A;Parnandi N;He Y;Zheng XF;Botuyan MV;Kalousi A;Yewdell WT;Münch C;Harper JW;Chaudhuri J;Soutoglou E;Mer G;Chowdhury D
通讯作者：
Chowdhury D

Cutting Edge: The Transcription Factor Sox2 Regulates AID Expression in Class-Switched B Cells.