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（由适用提供）：常见的脆弱位点（CFS）是大染色体区域，在复制应力后，会在中期染色体上裸露间隙并断裂。它们在癌症发展的早期阶段不稳定，并且通常与癌症的染色体重排有关。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，从而防止癌症发展。在这项研究中，我们建议研究DNA损伤检查点和DNA双链破裂（DSB）修复网络功能的潜在机制，以保持CFSS的基因组完整性。首先，我们将研究复制机制和复制检查点在保护CFSS的停滞复制叉中的作用。我们还将研究复制叉回归的参与，以去除CFSS的DNA二级结构并保护叉稳定性。其次，我们将使用新建立的基于EGFP的维修基板来研究用于维修与CFS相关的DSB的途径。由于途径选择会影响CFSS的修复保真度和基因组稳定性，因此了解保护CFSS的DSB修复机制对于揭示CFSS癌症相关的DNA病变的原因极为重要。第三，癌基因表达会引起CFS的不稳定性，但尚不清楚这种不稳定性如何导致容易发生癌症的DNA病变。我们将研究对癌基因表达形成的DNA病变的类型，并探测DNA修复的作用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。这些研究将大大帮助了解与CFS相关的癌症发展机制，并提供对癌症病因的见解。它们还将有助于制定新的治疗策略，以防止CFS相关的肿瘤发生。