DNA double-strand break repair, chromosome translocations and cancer

DNA双链断裂修复、染色体易位和癌症

• 批准号: 10394193
• 负责人: JEAN GAUTIER
• 金额: $ 174.71万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394193
• 关键词: 3-Dimensional; ATM deficient; Actins; Address; Affect; Automobile Driving; BRCA1 gene; Biochemistry; Cell Cycle; Cell Cycle Stage; Cell Nucleus; Cellular biology; Chromatin; Chromosomal Rearrangement; Chromosomal translocation; Chromosomes; Collaborations; Complex; Computational Biology; Computer Analysis; DNA; DNA Adducts; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA Sequence; DNA Topoisomerases; DNA biosynthesis; DNA lesion; DNA replication fork; Data; Defect; Development; Double Strand Break Repair; Etiology; Excision; Experimental Neoplasms; Funding; Genes; Genetic; Genome; Genomic Instability; Genomic Segment; Genomic approach; Genomics; Goals; Human; Immunoglobulins; Lesion; Light; Lymphocyte; Lymphoma; Malignant Neoplasms; Mammalian Cell; Maps; Molecular Analysis; Mutate; Mutation; Mutation Analysis; Nature; Nuclear; Outcome; Pathogenicity; Pathologic; Pathway interactions; Pattern; Phase; Phosphotransferases; Physiological; Poisoning; Process; Proteins; Recording of previous events; Repetitive Sequence; Replication Error; Ribosomal DNA; Signal Pathway; Signal Transduction; Single-Stranded DNA; Source; T-Cell Receptor; Technology; Topoisomerase; Topoisomerase Inhibitors; Transact; Tumor Suppressor Proteins; Wiskott-Aldrich Syndrome; Yeast Model System; Yeasts; cancer genome; cancer type; cell type; chemotherapeutic agent; chemotherapy; clinically relevant; experimental analysis; genome editing; genotoxicity; in vivo; mouse model; next generation; programs; repaired; response; stressor; telomere; tumor; tumorigenesis; tumorigenic

The genetic lesions that promote tumorigenesis, including chromosomal rearrangements, are generated primarily by illegitimate DNA repair. In this renewal application, we will continue to investigate the pathological consequences of aberrant DNA double-strand break (DSB) repair. This highly collaborative and integrated program will elucidate how DNA sequence, chromatin accessibility and nuclear organization influence the fate and pathological outcomes of DSBs in a cell type and cell cycle dependent manner. We will continue to use a combination of genetics in yeast and mouse models, biochemistry and cell biology. The application of next generation technologies together with high-throughput genomics approaches provides an unprecedented wealth of information about genomic instability in cancer genomes. We propose to leverage our multifaceted experimental approach with the strong genomics and computational biology components that pervade the Program. Drs. Rabadan and Baer will study mutation signatures - the statistically enriched patterns of DNA substitutions and rearrangements common across tumors - associated with specific BRCA1 deficiencies. They will also characterize mutation signatures generated by the other three Projects. Collectively these data will help deconvolute the complex mutational landscape of human tumors. Drs. Symington and Ciccia will address the nature of the initiating DNA lesions resulting in chromosome rearrangements, focusing on DNA replication errors in repair-deficient yeast and genome-edited mammalian cells. Dr. Sha will connect chromatin accessibility, locally and globally, with its propensity to break and yield translocations; pathological translocations at the immunoglobulin and T cell receptor loci during lymphocyte maturation fuel lymphoma development. Specifically, Dr. Zha will elucidate how ATM deficiencies favor translocations in a cell type and cell cycle dependent manner. Finally, Drs. Gautier and Gottesman will study how the spatial organization of the nucleus modulates DNA repair. Specifically, they will determine how nuclear actin and WASP, the gene mutated in Wiskott-Aldrich Syndrome, enables resection and influences chromosome translocations following DSBs or genotoxic lesions triggered by topoisomerase inhibition. The four Projects will be supported by two scientific Cores. All leaders and co-leaders have a strong history and record of productive collaboration.

产生促进肿瘤发生的遗传损伤，包括染色体重排， 主要是通过非法的DNA修复在这次更新申请中，我们将继续调查病理性 异常DNA双链断裂（DSB）修复的后果。这种高度协作和集成的 该计划将阐明DNA序列，染色质可及性和核组织如何影响命运 和病理结果的DSB的细胞类型和细胞周期依赖性的方式。我们将继续使用 酵母和小鼠模型中的遗传学、生物化学和细胞生物学的组合。Next的应用 新一代技术与高通量基因组学方法一起提供了前所未有的财富 关于癌症基因组不稳定性的信息。我们建议利用我们多方面的 实验方法与强大的基因组学和计算生物学组件，弥漫在 程序. Rabadan博士和Baer博士将研究突变特征--DNA的统计富集模式 在肿瘤中常见的取代和重排-与特定的BRCA 1缺陷相关。他们 还将描述其他三个项目产生的突变特征。这些数据将有助于 去卷积人类肿瘤的复杂突变景观赛明顿博士和西西亚博士将在 导致染色体重排的起始DNA损伤的性质，重点关注DNA复制错误 修复缺陷酵母和基因组编辑的哺乳动物细胞。沙博士将连接染色质可及性，本地 在全球范围内，由于其倾向于破坏和产生易位， 免疫球蛋白和T细胞受体基因座在淋巴细胞成熟燃料淋巴瘤发展。具体而言， 博士查将阐明如何ATM缺陷有利于易位的细胞类型和细胞周期依赖的方式。 最后，Gautier和Gottesman博士将研究细胞核的空间组织如何调节DNA修复。 具体来说，他们将确定核肌动蛋白和WASP（Wiskott-Aldrich综合征中突变的基因）， 能够切除并影响DSB后的染色体易位或由DSB引发的遗传毒性病变 拓扑异构酶抑制这四个项目将得到两个科学核心的支持。所有领导人和共同领导人 拥有良好的合作历史和记录。