RAG-induced DNA damage: mechanisms and responses

RAG 诱导的 DNA 损伤：机制和反应

• 批准号: 7362417
• 负责人: DAVID B. ROTH
• 金额: $ 29.05万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7362417
• 关键词: Apoptosis; Chromosomal translocation; Chromosomes; Collaborations; Complement; Complex; DNA; DNA Damage; DNA Sequence Rearrangement; Data; Defect; Development; Event; Frequencies; GRB10 gene; Generations; Genes; Genetic Recombination; Genome Stability; Genomics; Goals; Human; Individual; Knock-in Mouse; Laboratories; Lead; Lymphocyte; Lymphoma; Malignant Neoplasms; Measures; Mediating; Molecular; Monitor; Mus; Mutation; Nature; Nonhomologous DNA End Joining; Oncogenic; Pathogenesis; Pathway interactions; Peptide Signal Sequences; Process; Proteins; Proto-Oncogenes; Reaction; Role; Safety; Testing; Time; V(D)J Recombination; VDJ Recombinases; Work; cell growth; day; homologous recombination; in vivo; interest; leukemia/lymphoma; lymphoid neoplasm; mutant; novel; prevent; recombinase; repaired; research study; response; scaffold; sensor

DESCRIPTION (provided by applicant): We are interested in the safety mechanisms that prevent chromosome translocations that lead to the generation of lymphomas and leukemias, which are among the most common human cancers. With millions of lymphocytes undergoing V(D)J recombination each day, there are many opportunities for genomic integrity to be breached over the course of an individual's lifetime-- and chromosomal translocations are, in fact, a cardinal feature of lymphoid neoplasms. These rearrangements typically place an intact proto-oncogene under the regulatory control of the highly expressed Ig or TCR genes, leading to deleterious effects on cell growth, differentiation, or apoptosis. Compelling circumstantial evidence has implicated the V(D)J recombinase in these translocations, but how it might actually participate in aberrant rearrangements has remained mysterious. The Roth laboratory has recently made several discoveries that suggest novel mechanisms for V(D)J recombination-initiated aberrant rearrangements. We have also uncovered a new control point in the reaction that may prevent these events. The overarching goal of the studies proposed here is to understand the mechanisms that preserve genomic stability in lymphocytes and to define the molecular pathogenesis of V(D)J recombination-associated oncogenic rearrangements. To do so we will 1) probe the nature of the post-cleavage complex's scaffolding role; 2) examine the contribution of alternative RAG cleavage mechanisms to aberrant rearrangements; 3) create two lines of knock-in mice bearing RAG mutations we predict will increase the likelihood of aberrant rearrangements; 4) delineate the specific contributions of DNA damage sensors, checkpoint functions and the V(D)J recombinase to maintaining genomic stability. The last aim is in collaboration with the Petrini lab and capitalizes on their recent work implicating the Mrel I complex in controlling the fidelity of V(D)J recombination.

描述（由申请人提供）：我们对防止染色体易位的安全机制感兴趣，这些机制导致淋巴瘤和白血病的产生，这是最常见的人类癌症之一。每天有数百万个淋巴细胞经历V（d）J重组，因此在一个人的一生过程中，基因组完整性有很多机会 - 实际上，染色体易位是淋巴样肿瘤的主要特征。这些重排通常将完整的原型癌元放在高度表达的Ig或TCR基因的调节控制下，从而对细胞生长，分化或凋亡产生有害影响。令人信服的间接证据暗示了V（d）J重组酶在这些易位中，但是它实际上可能参与异常重排仍然神秘。罗斯实验室最近发现了一些发现，这些发现提出了V（d）J重组引发的异常重排的新机制。我们还发现了反应中的一个新控制点，可以防止这些事件。这里提出的研究的总体目标是了解保留淋巴细胞基因组稳定性的机制，并定义V（d）J重组相关的致癌重排的分子发病机理。为此，我们将1）探测裂解后复合物的脚手架作用的性质； 2）检查替代抹布裂解机制对异常重排的贡献； 3）创建两行的敲入小鼠轴承抹布突变，我们预测将增加异常重排的可能性； 4）描述DNA损伤传感器，检查点功能和V（d）J重组酶对维持基因组稳定性的特定贡献。最后的目标是与彼得里尼实验室合作，并利用了他们最近的工作，这意味着MREL I Complex控制V（d）J重组的忠诚度。