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（由申请人提供）：常见脆弱位点（CFS）是大的染色体区域，在复制应激时在中期染色体上表现出间隙和断裂。它们在癌症发展的早期阶段不稳定，并且通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，因此了解如何保护 CFS 以维持基因组稳定性，从而预防癌症发展非常重要。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持 CFS 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 CFS 中停滞的复制叉中的作用。我们还将研究复制叉回归在去除 CFS 处的 DNA 二级结构和保护复制叉稳定性方面的作用。其次，我们将使用新建立的基于 EGFP 的修复底物来研究用于修复与 CFS 相关的 DSB 的途径。由于途径选择会影响 CFS 的修复保真度和基因组稳定性，因此了解保护 CFS 的 DSB 修复机制对于揭示 CFS 癌症相关 DNA 损伤的原因极其重要。第三，癌基因表达会导致 CFS 不稳定，但这种不稳定如何导致易患癌症的 DNA 损伤仍不清楚。我们将研究癌基因表达时形成的 DNA 损伤类型，并探讨 DNA 修复和检查点网络在预防 CFS 中癌基因诱导的基因组不稳定中的作用。 这些研究将极大地帮助了解与 CFS 相关的癌症发展机制，并提供对癌症病因学的深入了解。他们还将帮助开发新的治疗策略来预防慢性疲劳综合症相关的肿瘤发生。