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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.

摘要当遇到抗原时，成熟的B细胞表达活化诱导的胞苷脱氨酶（AID），并经历免疫球蛋白重链（Igh）类别转换重组（CSR）和体细胞超突变（SHM）。CSR 通过DNA双链断裂（DSB）的专性产生进行，这构成了大多数毒性损伤都可能发生在细胞中。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的标志，包括淋巴瘤。因此，在本发明中，促进DSB产生和促进DSB修复的机制与免疫和保持基因组的完整性。在这个建议中，我们测试的概念，单一的蛋白质可以协调两者 DSB形成和介导末端连接以有效地产生和修复DSB。我们检验了一个假设，核小体重塑蛋白CHD 4协调Igh DSB的产生和修复（aim 1），而C- AID末端介导Igh DSB的有效DNA修复（目的2）。成功完成实验将对我们理解B细胞免疫和B细胞淋巴瘤产生深远的影响。

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.