Mechanism of Class Switch Recombination

类切换重组机制

• 批准号: 8891660
• 负责人: Kefei Yu
• 金额: $ 34.04万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891660
• 关键词: Address; Antibodies; B-Cell Neoplasm; Biology; Cells; Chromosomal translocation; Cytosine; DNA; DNA Ligases; DNA lesion; Deamination; Elements; Enhancers; Event; Frequencies; Gene Conversion; Genetic Recombination; Genetic Transcription; Genome; Genomics; Health; Hematopoietic Neoplasms; Immune System Diseases; Immune system; Immunoglobulin Class Switching; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Infection; Knowledge; Lesion; Mediating; Mutation; Oncogenic; Pathology; Positioning Attribute; Production; Reaction; Transcriptional Regulation; Uracil; activation-induced cytidine deaminase; in vivo; promoter

DESCRIPTION (provided by applicant): Activation-induced cytidine deaminase (AID) initiates immunoglobulin gene somatic hypermutation, gene conversion and class switch recombination (CSR) by inflicting DNA lesions at specific genomic loci via DNA cytosine deamination (that converts cytosine to uracil). While these lesions are essential for the production of optimized antibodies against infections, they are also threats to the genome integrity. AID-associated oncogenic mutations and chromosomal translocations are frequently seen in tumors of B cell origin. We propose three specific aims to address several significant gaps in our knowledge about the mechanism of CSR. In aim 1, we will manipulate the transcription control elements (promoters/enhancers) at IgH α locus in CH12F3 cells to identify cis-acting DNA elements critical for targeting AID to switch (S) regions. In aim 2, we will determine the frequency and precise positions of AID footprints in S regions to delineate AID actions in vivo during CSR. In aim 3, we will determine which DNA ligase is responsible for alternative end-joining of S region breaks.

描述(申请人提供)：激活诱导型胞苷脱氨酶(AID)通过DNA胞嘧啶脱氨作用(将胞嘧啶转化为尿嘧啶)在特定的基因组座位上造成DNA损伤，从而启动免疫球蛋白基因的体细胞超突变、基因转换和类别切换重组(CSR)。虽然这些损伤对于产生优化的抗感染抗体是必不可少的，但它们也是对基因组完整性的威胁。与艾滋病相关的致癌突变和染色体易位常见于B细胞起源的肿瘤。我们提出了三个具体目标，以解决我们对企业社会责任机制认识上的几个重大差距。在目标1中，我们将操纵CH12F3细胞中IgHα基因座的转录调控元件(启动子/增强子)，以确定与靶向艾滋病转开关(S)区域至关重要的顺式作用元件。在目标2中，我们将确定艾滋病足迹在S区域的频率和精确位置，以描绘艾滋病在CSR期间在体内的作用。在目标3中，我们将确定哪个DNA连接酶负责S区域断裂的选择性末端连接。

项目成果

The SAGA Deubiquitination Module Promotes DNA Repair and Class Switch Recombination through ATM and DNAPK-Mediated γH2AX Formation.

• DOI: 10.1016/j.celrep.2016.04.041
• 发表时间: 2016-05-17
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Ramachandran S;Haddad D;Li C;Le MX;Ling AK;So CC;Nepal RM;Gommerman JL;Yu K;Ketela T;Moffat J;Martin A
• 通讯作者: Martin A