Study the mechanisms underlying common fragile site protection

研究常见脆弱点保护的机制

• 批准号: 9118932
• 负责人: Xiaohua Wu
• 金额: $ 44.03万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118932
• 关键词: AT Rich Sequence; Affect; Applications Grants; Cancer Etiology; Chromosomal Rearrangement; Chromosome Breakage; Chromosome Fragile Sites; Chromosome Structures; Chromosomes; Complex; DNA; DNA Double Strand Break; DNA Repair; DNA Sequence; DNA biosynthesis; DNA damage checkpoint; DNA lesion; DNA replication fork; Development; Diagnostic Neoplasm Staging; Double Strand Break Repair; Exhibits; Fanconi anemia protein; Gene Amplification; Generations; Genome Stability; Genomic Instability; Health; Human; Individual; Maintenance; Malignant Neoplasms; Mediating; Metaphase; Mitotic Recombination; Molecular; Nonhomologous DNA End Joining; Oncogenes; Oncogenic; Pathway interactions; Prevention; Process; Regulation; Research Design; Role; Stress; Structure; Therapeutic; base; c-myc Genes; cancer prevention; design; driving force; genome integrity; homologous recombination; insight; novel; novel therapeutics; prevent; repaired; tumorigenesis

 DESCRIPTION (provided by applicant): Common fragile sites (CFSs) are large chromosomal regions that exhibit gaps and breaks on metaphase chromosomes upon replication stress. They are unstable at early stages of cancer development and are often associated with chromosomal rearrangements in cancer. Since CFSs are part of the normal chromosomes, it is important to understand how CFSs are protected to maintain genome stability, thereby preventing cancer development. In this study, we propose to investigate the underlying mechanisms of how DNA damage checkpoint and DNA double-strand break (DSB) repair networks function to preserve genome integrity at CFSs. First, we will study the role of the replication machinery and replication checkpoints in the protection of stalled replication forks at CFSs. We will also investigate the involvement of replication fork regression in removing DNA secondary structures at CFSs and protecting for fork stability. Second, we will use our newly established EGFP-based repair substrates to study the pathways that are utilized to repair DSBs associated with CFSs. Since pathway choice would influence repair fidelity and genome stability at CFSs, understanding the DSB repair mechanisms to protect CFSs is extremely important for revealing the cause of cancer-related DNA lesions at CFSs. Third, oncogene expression induces CFS instability, but it remains unknown how such instability leads to cancer-prone DNA lesions. We will study the types of DNA lesions formed upon oncogene expression, and probe the roles of DNA repair and the checkpoint network in the prevention of oncogene-induced genome instability at CFSs. These studies will significantly help understand the mechanisms of cancer development that is associated with CFSs, and provide insight into cancer etiology. They will also help develop novel therapeutic strategies to prevent CFS-associated tumorigenesis.

 描述(申请人提供)：常见的脆性部位(CFS)是指在复制压力下中期染色体上出现缺口和断裂的大的染色体区域。它们在癌症发展的早期阶段是不稳定的，经常与癌症中的染色体重排有关。由于CFS是正常染色体的一部分，因此了解CFS如何受到保护以维持基因组的稳定，从而防止癌症的发展是很重要的。在这项研究中，我们建议研究DNA损伤检查点和DNA双链断裂(DSB)修复网络如何发挥作用以保护CFSS基因组完整性的潜在机制。首先，我们将研究复制机制和复制检查点在保护CFSS中停滞的复制分叉中的作用。我们还将研究复制分支回归在移除CFSS的DNA二级结构和保护分支稳定性中的作用。其次，我们将使用我们新建立的基于绿色荧光蛋白的修复底物来研究用于修复与CFSS相关的DSB的途径。由于途径的选择会影响CFSS的修复保真度和基因组稳定性，了解DSB修复机制以保护CFSS对于揭示CFSS癌症相关DNA损伤的原因至关重要。第三，癌基因表达诱导CFS不稳定，但这种不稳定如何导致易癌的DNA损伤仍不清楚。我们将研究由癌基因表达形成的DNA损伤的类型，并探讨DNA修复和检查点网络在预防癌基因诱导的CFSS基因组不稳定性中的作用。这些研究将大大有助于理解与CFSS相关的癌症发展机制，并为癌症病因学提供洞察力。他们还将帮助开发新的治疗策略，以防止CFS相关的肿瘤发生。