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（由申请方提供）：常见脆性位点（CFS）是在复制强制降解后中期染色体上显示间隙和断裂的大染色体区域。它们在癌症发展的早期阶段是不稳定的，并且通常与癌症中的染色体重排有关。由于CFSs是正常染色体的一部分，因此了解CFSs如何被保护以维持基因组稳定性，从而防止癌症发展是很重要的。在这项研究中，我们建议调查DNA损伤检查点和DNA双链断裂（DSB）修复网络的功能，以保持基因组的完整性在CFS的潜在机制。 首先，我们将研究的作用，复制机制和复制检查点在保护停滞的复制叉在CFS。我们还将研究复制叉回归在去除CFSs的DNA二级结构和保护叉稳定性中的参与。其次，我们将使用我们新建立的基于EGFP的修复底物来研究用于修复与CFS相关的DSB的途径。由于途径的选择会影响CFS的修复保真度和基因组稳定性，因此了解DSB修复机制以保护CFS对于揭示CFS处癌症相关DNA损伤的原因至关重要。第三，癌基因表达诱导CFS不稳定性，但仍不清楚这种不稳定性如何导致癌症倾向的DNA损伤。我们将研究癌基因表达后形成的DNA损伤类型，并探讨DNA修复和检查点网络在预防癌基因诱导的基因组不稳定性中的作用。 这些研究将显著帮助理解与CFS相关的癌症发展机制，并提供对癌症病因学的见解。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。