DNA double-strand break repair, chromosomes translocations and cancer

DNA 双链断裂修复、染色体易位和癌症

• 批准号: 9241973
• 负责人: JEAN GAUTIER
• 金额: $ 177.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-08 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241973
• 关键词: Affect; Animals; B-Lymphocytes; BRCA1 gene; Binding; Biochemical; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Carcinogenesis; Breast Epithelial Cells; Cells; Chromosomal Instability; Chromosomal Rearrangement; Chromosomal translocation; Chromosomes; Collaborations; Cyclin-Dependent Kinases; DNA; DNA Adducts; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA Restriction Enzymes; Data; Development; Disease; Double Strand Break Repair; Engineering; Epithelial; Event; Excision; Genetic; Genetic Transcription; Genetic study; Genome Stability; Genomic Instability; Goals; Human; Joints; Lead; Lymphocyte; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Malignant lymphoid neoplasm; Mammalian Cell; Mammary Neoplasms; Mediating; Modeling; Molecular Analysis; Mus; Mutation; Nonhomologous DNA End Joining; Oncogenic; Pathogenicity; Pathology; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Process; Proteins; Recording of previous events; Recurrence; Regulation; Role; Single-Stranded DNA; Solid Neoplasm; TP53 gene; Technology; Testing; Topoisomerase Inhibitors; Training; Tumorigenicity; V(D)J Recombination; Xenopus; Yeasts; c-myc Genes; cohesion; genetic analysis; genome-wide; interest; loss of function; lymphoid neoplasm; malignant breast neoplasm; mouse model; mutant; overexpression; prevent; programs; repaired; response; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): DNA double-strand break (DSB) repair prevents persistent DNA damage, counteracts genome instability and suppresses tumor development. However, DSB repair also has the potential to produce oncogenic chromosome translocations and rearrangements. This highly integrated program will elucidate the mechanism and regulation of DSB repair initiation and its impact on DSB repair choice, chromosome translocation and cancer development in model of lymphoma and breast cancer. In particular, the program will investigate the regulation of microhomology-mediated end-joining (MMEJ), a pathogenic form of DSB repair responsible for a significant fraction of tumorigenic chromosome translocations. Preliminary studies from all projects focusing on DNA processing and CtIP have generated a focused and cohesive program. Dr. Symington will use genetic analysis to assess how DNA resection affects MMEJ and to investigate the competition between MMEJ and other modes of DSB repair. Dr. Symington will also develop sensitive physical resection assays in mammalian cells, a technology which is notably lacking at present. Drs. Gautier and Gottesman will study the mechanism(s) that generate persistent, short ssDNA overhangs at DSBs, an intermediate involved in MMEJ. Their studies will focus on the role of CtIP, a protein involved in initiation of DNA resection. In the third project, Drs. Zha and Dalla-Favera will evaluate the role of CtIP in repair of programmed DSBs during lymphocyte development and malignancy. They will also test the hypothesis that CtIP mediates, at least in part, the oncogenic function of c-Myc including its undefined role in genomic instability. Dr. Baer, will determine how CtIP facilitates breast tumor development in p53-deficient mice and will test whether CtIP loss can also suppress basal-like breast cancer in BRCA1-deficient mice. Finally, he will evaluate the potential role of CtIP in Myc-driven breast tumor development. To accomplish these goals, the projects will rely extensively on three interlinked cores: administrative, molecular analysis of genomic instability and pathology. The project and core leaders have a very strong history of collaboration, joint efforts in training and common interests in genome stability and the mechanisms of its loss in cancer.

描述（由申请人提供）：DNA双链断裂（DSB）维修可防止持续的DNA损伤，抵消基因组不稳定性并抑制肿瘤的发育。但是，DSB维修还具有产生致癌染色体易位和重排的潜力。这个高度综合的计划将阐明DSB修复起始的机制和调节及其对DSB修复选择，染色体易位和癌症发展的影响。特别是，该计划将调查微型学介导的最终结合（MMEJ）的调节，这是一种DSB修复的致病形式，负责大量的致瘤染色体易位。所有专注于DNA处理和CTIP的项目的初步研究都产生了一个集中和凝聚力的计划。 Symington博士将使用遗传分析来评估DNA切除如何影响MMEJ并研究MMEJ和其他DSB修复模式之间的竞争。 Symington博士还将在哺乳动物细胞中开发敏感的身体切除测定法，这项技术目前尤其缺乏。博士。 Gautier和Gottesman将研究在DSB处产生持久的短ssDNA悬垂的机制，DSB是一个参与MMEJ的中间体。他们的研究将集中于CTIP的作用，CTIP是与DNA切除启动有关的蛋白质。在第三个项目中，博士。 Zha和Dalla-Favera将评估该角色 在淋巴细胞发育和恶性肿瘤期间修复编程DSB的CTIP的CTIP。他们还将检验以下假设：CTIP至少部分地介导了C-MYC的致癌功能，包括其在基因组不稳定性中的不确定作用。 Baer博士将确定CTIP如何促进p53缺陷小鼠的乳腺肿瘤发展，并将测试CTIP损失是否也可以抑制BRCA1缺陷小鼠的基础样乳腺癌。最后，他将评估CTIP在MYC驱动的乳腺肿瘤发育中的潜在作用。为了实现这些目标，这些项目将广泛依赖三个相互联系的核心：基因组不稳定性和病理学的行政，分子分析。该项目和核心领导者的合作历史，在培训方面的共同努力和基因组稳定性的共同利益以及其癌症丧失的机制。