Elucidation of Immunoglobulin Class Switch Recombination

免疫球蛋白类别转换重组的阐明

• 批准号: 9172233
• 负责人: Jayanta Chaudhuri
• 金额: $ 43.98万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172233
• 关键词: Alpha Cell; Antibodies; B-Cell Lymphomas; B-Lymphocytes; Base Excision Repairs; Binding; Biological Models; Cell Death; Cells; Chromosomal translocation; Coupling; Cyclic AMP-Dependent Protein Kinases; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Data; Deaminase; Deamination; Defect; Deoxycytidine; Deoxyuridine; Double Effect; Double Strand Break Repair; Elements; Endonuclease I; Ensure; Excision; Exons; Failure; Feedback; G1 Phase; Generations; Genetic Recombination; Growth; Human; IgE; Immune response; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin Constant Region; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Switch Recombination; Immunologic Deficiency Syndromes; Impairment; In Vitro; Intuition; Invaded; Lead; Lesion; Lymphoma; Lymphomagenesis; Mature B-Lymphocyte; Mediating; Mismatch Repair; Modeling; Molecular; Organism; Pathway interactions; Phosphorylation; Play; Process; Proteins; Reaction; Recruitment Activity; Repetitive Sequence; Role; Serine; Single-Stranded DNA; Site; System; Testing; Uracil; activation-induced cytidine deaminase; arm; base; cancer type; constant region gene; density; endodeoxyribonuclease SceI; endonuclease; in vivo; insight; mutant; novel; pathogen; phosphodiester; public health relevance; repair enzyme; repaired; response; sensor; single molecule; uracil-DNA glycosylase

DESCRIPTION (provided by applicant): Mature B-lymphocytes undergo class switch recombination (CSR), a deletional-recombination reaction that replaces the constant region of the immunoglobulin (Ig) molecule for one of a set of downstream constant region genes. This changes the class of the expressed antibody from IgM to IgG, IgE or IgA, each of which has distinct effector functions. CSR occurs within and requires large repetitive sequences termed switch (S) regions that precede the constant region genes. CSR is initiated by AID (activation induced deaminase), a single-strand DNA-specific deaminase, that introduces U:G mismatches in transcribed S regions. Subsequent processing by components of base excision repair and mismatch repair pathways introduces DNA double- stranded breaks (DSBs) in S regions. DSBs between two distinct S regions are synapsed and then ligated by end-joining. DSBs serve as obligatory intermediates of CSR; however, DSBs also constitute one of the most toxic lesions that can occur in a cell. A single unrepaired DSB can lead to cell death or can participate in chromosomal translocations, the hallmarks of many types of cancer, including lymphomas. Thus, CSR requires not only the generation but also efficient repair of DSBs. In this proposal we test the hypothesis that phosphorylation of AID plays an essential role in the generation of DSBs. We also explore the hypothesis that the DNA damage sensor ATM participates in inducing AID phosphorylation and repair of DSBs during the process. Impaired CSR leads to impaired ability to respond to pathogens while aberrant CSR is one of the major underlying factors in the ontogeny of B cell lymphomas. Our studies will thus have major impact on both immunodeficiency syndromes and B cell lymphomagenesis.

描述（由申请人提供）：成熟b淋巴细胞进行类开关重组（CSR），这是一种缺失重组反应，将免疫球蛋白（Ig）分子的恒定区替换为一组下游恒定区基因之一。这将表达的抗体类别从IgM改变为IgG、IgE或IgA，每种抗体都具有不同的效应功能。CSR发生在恒定区基因之前的称为开关(S)区域的大型重复序列中。CSR是由AID（激活诱导脱氨酶）启动的，AID是一种单链dna特异性脱氨酶，在转录的S区引入U:G错配。碱基切除修复和错配修复途径的后续处理在S区引入了DNA双链断裂（dsb）。两个不同的S区之间的dsb突触，然后通过末端连接连接。争端解决机构是企业社会责任的强制性中介机构；然而，dsb也是细胞中毒性最强的病变之一。单个未修复的DSB可导致细胞死亡或参与染色体易位，染色体易位是包括淋巴瘤在内的许多类型癌症的标志。因此，CSR不仅需要生成dsb，还需要有效修复dsb。在这个提议中，我们检验了AID的磷酸化在dsb的产生中起重要作用的假设。我们还探讨了DNA损伤传感器ATM参与诱导AID磷酸化和dsb修复的假设。CSR受损导致对病原体的反应能力受损，而CSR异常是B细胞淋巴瘤发生的主要潜在因素之一。因此，我们的研究将对免疫缺陷综合征和B细胞淋巴瘤产生重大影响。