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)：免疫的B系细胞的独特之处在于，在免疫反应期间，它们在免疫球蛋白基因座上经历发育程序性DNA双链断裂(DSB)，以便在称为类切换重组(CSR)的过程中产生功能性抗体。因此，切换B细胞为研究细胞对生理性DSB的反应提供了一个很好的模型。正在经历CSR的B细胞触发DNA损伤反应(DDR)途径，该途径向细胞发出信号，暂停和修复DNA断裂，或者如果无法解决损伤，则进行细胞凋亡。DDR通路是细胞对DNA损伤的初始反应，在肿瘤发生的早期被激活，但在进展为癌症时经常丢失。在CSR过程中，DDR途径的中断会导致B细胞免疫球蛋白转换受损，并导致涉及IgH基因的染色体易位。共济失调-毛细血管扩张症突变基因(ATM)是感知和响应DNA损伤的关键协调者。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基因的染色体易位。在这方面，在许多淋巴系恶性肿瘤中都发现了ATM的改变。ATM在维持B系细胞基因组稳定性中的确切作用尚不清楚。在这项提案中，我们试图开发方法来研究ATM募集对经历类别转换的B细胞中程序性DNA断裂的调节机制。DSB修复复合体的定位和分子评估将阐明CSR过程中DDR的成分。此外，我们将研究参与主动免疫反应的确定的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，我们将进一步测试有助于ATM招募到IgH基因座的准确DNA序列。综上所述，这些研究将进一步确定调节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-毛细血管扩张症患者死亡的主要原因。这项建议中的研究试图了解促进致癌事件B细胞的基本机制，这也适用于AT患者发生的其他癌症。这些发现可能会导致开发新的、合理的治疗AT患者癌症的靶点。