Role of Telomeric Proteins in Antibody Class Switch Recombination

端粒蛋白在抗体类别转换重组中的作用

• 批准号: 8915932
• 负责人: Ramiro Ernesto Verdun
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915932
• 关键词: Address; Adverse effects; Affect; Affinity; Alleles; Antibodies; B lymphoid malignancy; B-Lymphocytes; Bacteria; Binding; Biological Assay; Biological Models; Cell Line; Cell Maintenance; Chromatin; Chromosomal translocation; Chromosomes; Complement; Complex; Cytosine deaminase; DNA; DNA Binding; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA lesion; Data; Deaminase; Enzyme Activation; Event; Exhibits; G22P1 gene; Generations; Genes; Genetic Recombination; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Health; IGH@ gene cluster; Immune; Immune response; Immune system; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; In Vitro; Knockout Mice; Knowledge; Lead; Lesion; Lymphocyte; Lymphoma; Mediating; Molecular; Mus; Mutate; Mutation; Nonhomologous DNA End Joining; Oncogenes; Pathway interactions; Process; Proteins; Proto-Oncogenes; Regulation; Research; Research Project Grants; Research Proposals; Role; Sequence Analysis; Serological; Structure; Telomeric Repeat Binding Protein 2; Tertiary Protein Structure; Virus; activation-induced cytidine deaminase; base; design; ds-DNA; mouse model; mutant; novel; novel therapeutics; pathogen; programs; repaired; response; telomere

DESCRIPTION (provided by applicant): Antibody (immunoglobulin, Ig) class switch recombination (CSR) is an essential mechanism for the diversification of humoral immune response through efficient generation of antibody isotypes that mediate elimination of pathogens. CSR is a programmed deletional recombination event between DNA double strand breaks (DSBs) at switch (S) regions in the Ig heavy chain gene locus (Igh). These DSBs are initiated by the mutagenic enzyme, activation-induced cytidine deaminase (AID), which preferentially localizes at Igh loci but also exhibits off-target activity in other genomic regions including proto-oncogenes. Hence, DSBs initiated by AID in off-target regions of the genome can readily lead to aberrant recombination events and chromosome translocations between the Igh locus and oncogenes if not correctly repaired. Indeed, such genomic aberrations are a hallmark of B-cell malignancies. However the molecular mechanisms that define how B-cells control the repair of DNA lesions initiated by AID are poorly understood. Accordingly the goal of our research proposal is to characterize novel molecular mechanisms we have identified that regulate the repair of DNA lesions initiated by AID during CSR. We recently discovered that the telomeric protein TRF2, which is essential for protecting chromosome ends from DNA repair activity, is also needed for CSR. Here we propose to extend our studies to identify and characterize the molecular mechanisms utilized by TRF2 to control the CSR via the following specific aims: 1. Identify and characterize the specific DDR proteins regulated by TRF2 during CSR. 2. Dissect the molecular mechanisms used by TRF2 to control DNA repair during CSR. 3. Elucidate how TRF2 interacts with the Igh locus during CSR. Taken together, these studies will provide specific details into a novel mechanism that regulates immune diversification in B-cells and the maintenance of the genome stability during AID activation.

描述（由申请人提供）：抗体（免疫球蛋白，Ig）类开关重组（CSR）是体液免疫反应多样化的重要机制，通过有效产生介导病原体消除的抗体同型。CSR是在Ig重链基因位点（Igh）开关(S)区域DNA双链断裂（DSBs）之间发生的程序性缺失重组事件。这些dsb由诱变酶激活诱导胞苷脱氨酶（AID）启动，该酶优先定位于Igh位点，但在其他基因组区域也表现出脱靶活性