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) 修复可防止持续性 DNA 损伤、抵消基因组不稳定性并抑制肿瘤发展。然而，DSB 修复也有可能产生致癌染色体易位和重排。这个高度集成的项目将阐明 DSB 修复启动的机制和调节及其对淋巴瘤和乳腺癌模型中 DSB 修复选择、染色体易位和癌症发展的影响。特别是，该计划将研究微同源介导的末端连接（MMEJ）的调节，这是一种 DSB 修复的致病形式，负责大部分致瘤性染色体易位。所有专注于 DNA 处理和 CtIP 的项目的初步研究已经形成了一个重点突出且具有凝聚力的计划。 Symington 博士将利用遗传分析来评估 DNA 切除如何影响 MMEJ，并研究 MMEJ 与其他 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灵敏的物理切除测定法，这是目前明显缺乏的技术。博士。 Gautier 和 Gottesman 将研究 DSB（参与 MMEJ 的中间体）产生持久、短 ssDNA 突出端的机制。他们的研究将集中于 CtIP 的作用，CtIP 是一种参与启动 DNA 切除的蛋白质。在第三个项目中，博士。 Zha 和 Dalla-Favera 将评估该角色 CtIP 在淋巴细胞发育和恶性肿瘤过程中修复程序化 DSB 中的作用。他们还将检验以下假设：CtIP 至少部分介导 c-Myc 的致癌功能，包括其在基因组不稳定中的未明确作用。 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 缺失是否也能抑制 BRCA1 缺陷小鼠的基底样乳腺癌。最后，他将评估 CtIP 在 Myc 驱动的乳腺肿瘤发展中的潜在作用。为了实现这些目标，这些项目将广泛依赖三个相互关联的核心：基因组不稳定性和病理学的管理、分子分析。该项目和核心领导者有着悠久的合作历史、培训方面的共同努力以及对基因组稳定性及其在癌症中丧失的机制的共同兴趣。