DNA Damage Responses in B Cell Development

B 细胞发育中的 DNA 损伤反应

• 批准号: 7589351
• 负责人: JOHN P MANIS
• 金额: $ 22.12万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589351
• 关键词: ATM gene; ATM wt Allele; Affect; Antibodies; Apoptosis; Ataxia Telangiectasia; Attention; B-Cell Development; B-Cell Lymphomas; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Cause of Death; Cell Lineage; Cells; Chromatin Structure; Chromosomal translocation; Chromosome Pairing; Color; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Sequence; DNA Structure; Development; Double Strand Break Repair; Event; Fluorescent in Situ Hybridization; Frequencies; Gene Mutation; Generations; Genetic Transcription; Genome Stability; Human; IGH@ gene cluster; Immune; Immune response; Immunization; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunoglobulins; Immunohistochemistry; In Vitro; Induced Mutation; Ionizing radiation; Lead; Lymphoid Cell; Maintenance; Malignant Neoplasms; Malignant lymphoid neoplasm; Mature B-Lymphocyte; Methods; Modeling; Molecular; Mus; Oncogenic; Pathway interactions; Patients; Physiological; Population; Process; Proto-Oncogenes; Reaction; Recruitment Activity; Repair Complex; Role; Signal Transduction; Single-Stranded DNA; Site; Structure of germinal center of lymph node; Techniques; Testing; activation-induced cytidine deaminase; c-myc Genes; in vivo; insight; member; novel; programs; public health relevance; repaired; response; therapeutic target; tumorigenesis

DESCRIPTION (provided by applicant): B lineage cells of the immune are unique in their ability to undergo developmentally programmed DNA double strand breaks (DSB) within their immunoglobulin loci during an immune response in order to generate functional antibodies in a process termed class switch recombination (CSR). Switching B cells thus offer an excellent model to study cellular responses to physiologic DSB. B cells undergoing CSR trigger the DNA damage response (DDR) pathway, which signals cells to pause and repair DNA breaks, or if unable to resolve the damage to then undergo apoptosis. The DDR pathway is the initial cellular response to DNA damage, which is activated early in tumorigenesis but is frequently lost during progression to cancer. Disruption of the DDR pathway during CSR leads to impaired immunoglobulin switching in B cells and to chromosomal translocations involving the IgH locus. The ataxia-telangiectasia mutated gene (ATM) is the key coordinator of sensing and responding to DNA damage. B cells deficient for ATM have impaired CSR and frequently generate chromosomal translocations involving the immunoglobulin heavy chain locus. In this regard, ATM alterations have been detected in many lymphoid malignancies. The exact role of ATM in maintaining genomic stability in B lineage cells remains unknown. In this proposal we seek to develop methods to study the mechanisms that regulate ATM recruitment to programmed DNA breaks in B cells undergoing class switching. Localization and molecular assessment of the DSB repair complex will elucidate the components of the DDR during CSR. In addition we will examine defined populations of B cells participating in an active immune response to determine the specific populations in which ATM and other members of the DDR are recruited to the IgH locus. In our second aim, we will further test the exact DNA sequences that facilitate recruitment of ATM to the IgH locus. Taken together, these studies will further define the mechanisms that regulate the maintenance of genomic stability in ATM-deficient B cells, providing insights towards the development of therapeutic targets. PUBLIC HEALTH RELEVANCE: B cell lymphoma is a major cause of death in patients with ataxia-telangiectasia. The studies in this proposal seek to understand the basic mechanisms that promote oncogenic events B cells, which is also applicable towards other cancers that develop in AT patients. These findings may lead to the development of novel and rational therapeutic targets for cancer in patients with AT.

描述（由申请人提供）：免疫 B 谱系细胞的独特之处在于，它们能够在免疫反应期间在其免疫球蛋白位点内经历发育程序性 DNA 双链断裂 (DSB)，以便在称为类别转换重组的过程中产生功能性抗体（企业社会责任）。因此，转换 B 细胞为研究细胞对生理 DSB 的反应提供了一个极好的模型。经历 CSR 的 B 细胞会触发 DNA 损伤反应 (DDR) 通路，该通路向细胞发出信号以暂停并修复 DNA 断裂，或者如果无法解决损伤，则发生细胞凋亡。 DDR 途径是细胞对 DNA 损伤的最初反应，在肿瘤发生早期被激活，但在癌症进展过程中经常丢失。 CSR 过程中 DDR 通路的破坏会导致 B 细胞中的免疫球蛋白转换受损以及涉及 IgH 位点的染色体易位。共济失调毛细血管扩张突变基因 (ATM) 是感知和响应 DNA 损伤的关键协调子。缺乏 ATM 的 B 细胞会损害 CSR，并经常产生涉及免疫球蛋白重链位点的染色体易位。在这方面，已在许多淋巴恶性肿瘤中检测到 ATM 改变。 ATM 在维持 B 谱系细胞基因组稳定性方面的确切作用仍不清楚。在本提案中，我们寻求开发方法来研究调节 ATM 募集到经历类别转换的 B 细胞中程序性 DNA 断裂的机制。 DSB 修复复合体的定位和分子评估将阐明 CSR 期间 DDR 的组成部分。此外，我们将检查参与主动免疫反应的特定 B 细胞群体，以确定 ATM 和 DDR 的其他成员被招募到 IgH 基因座的特定群体。在我们的第二个目标中，我们将进一步测试促进 ATM 招募到 IgH 基因座的确切 DNA 序列。总而言之，这些研究将进一步明确调节 ATM 缺陷 B 细胞基因组稳定性维持的机制，为治疗靶点的开发提供见解。公共卫生相关性：B 细胞淋巴瘤是共济失调毛细血管扩张患者死亡的主要原因。该提案中的研究旨在了解促进 B 细胞致癌事件的基本机制，这也适用于 AT 患者中发生的其他癌症。这些发现可能会导致针对 AT 患者癌症的新的、合理的治疗靶点的开发。