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.

促进肿瘤发生的遗传病变，包括染色体重排