RNA-directed targeting of AID in immunity and cancer

RNA定向靶向AID在免疫和癌症中的作用

• 批准号: 10664029
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664029
• 关键词: Antigen Presentation; Antigens; B lymphoid malignancy; B-Cell Activation; B-Cell Lymphomas; B-Lymphocytes; Base Pairing; Binding; Cell Death; Cells; Cellular Immunity; Chromatin; Chromosomal translocation; Cytidine Deaminase; DNA; DNA Double Strand Break; DNA Structure; Deamination; Defect; Deoxycytidine; Deoxyuridine; Double Strand Break Repair; Exons; Failure; Funding; Future; G-Quartets; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Genome; Goals; Growth; Guanine; Guide RNA; Heavy-Chain Immunoglobulins; Human; Humoral Immunities; IGH@ gene cluster; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunologic Deficiency Syndromes; Induced Mutation; Ions; Knock-in Mouse; Knowledge; Lead; Lesion; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Memory B-Lymphocyte; Molecular Conformation; Mus; Mutate; Mutation; Oncogenic; Pathologic; Patients; Physiological; Plasma Cells; Process; Proteins; RNA; RNA Splicing; Reaction; Residencies; Rest; Role; Shelter facility; Structure; Structure of germinal center of lymph node; Testing; Text; Transcript; activation-induced cytidine deaminase; cancer type; experimental study; gene correction; genome integrity; genome-wide; humoral immunity deficiency; interest; large cell Diffuse non-Hodgkin' s lymphoma; novel; preservation; recruit; response

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 non-canonical DNA structures such as G-quadruplexes target the DNA deaminase AID to the chromatin during CSR (aim 1) and that AID can regulate expression of non-Ig genes to influence B cell responses (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。在这个提议中，我们测试了非规范DNA结构的概念， 因为G-四链体在CSR期间将DNA脱氨酶AID靶向染色质（aim 1），并且AID可以 调节非Ig基因的表达以影响B细胞应答（目的2）。成功完成 这些实验对我们理解B细胞免疫和B细胞免疫都有深远的意义。 淋巴瘤