Studying the mechanisms underlying the protection of common fragile sites and structure-prone DNA sequences

研究保护常见脆弱位点和易于结构的 DNA 序列的机制

• 批准号: 10437601
• 负责人: Xiaohua Wu
• 金额: $ 39.39万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437601
• 关键词: AT Rich Sequence; ATRX gene; Abbreviations; Address; Aphidicolin; Applications Grants; Cells; Chromatin Remodeling Factor; Chromosomal Rearrangement; Chromosome Fragile Sites; Chromosome Structures; Chromosomes; Colon Carcinoma; Colonic Neoplasms; Complex; DAXX gene; DNA; DNA Sequence; DNA biosynthesis; DNA replication fork; Deposition; Development; Double Strand Break Repair; ERCC1 gene; Exhibits; Foundations; Gene Conversion; Genome Stability; Human Genome; Lead; MSH2 gene; MSH3 gene; Maintenance; Malignant Neoplasms; Mammalian Cell; Mediating; Metaphase; Mismatch Repair; Mitotic; Mitotic Recombination; Modeling; Molecular; Molecular Chaperones; Mus; Pathway interactions; Polyacrylamide Gel Electrophoresis; Principal Investigator; Proteins; RAS genes; Reporter; Resistance; Role; Single-Stranded DNA; Structure; Testing; Work; base; cancer therapy; chemotherapy; chromatin immunoprecipitation; chromatin remodeling; genome-wide; homologous recombination; hydroxyurea; insight; neoplastic cell; novel; novel therapeutic intervention; preservation; prevent; programs; replication stress; targeted treatment; telomere; translocase; treatment strategy; tumor; tumor xenograft

Principal Investigator: Wu, Xiaohua Project Summary Studying the mechanisms underlying the protection of common fragile sites and structure- prone DNA sequences Project Summary/Abstract Common fragile sites (CFSs) are large chromosomal regions that often exhibit gaps and breaks on metaphase chromosomes upon replication stress. Structure-prone AT-rich sequences present at CFSs (CFS-ATs) contribute to CFS instability. Besides CFS-ATs, other structure-prone DNA sequences, such as G-quadruplexes (G4s), are also abundant in the human genome and are associated with chromosomal rearrangement breakpoints in cancer. Since CFSs and many structure-prone DNA sequences, including G4s, are part of normal chromosomal structures, it is important to understand how the integrity of these structure-prone DNA sequences is maintained in mammalian cells. In this grant application, we will use EGFP-based DSB repair reporters to investigate the mechanisms underlying the protection of structure-prone DNA sequences present at CFSs and G4s. We will study the role of chromatin-remodeling in the maintenance of CFSs and address the DSB repair mechanism specifically used to repair DSBs arising at DNA secondary structures upon fork collapse. We will also explore the functional coordination of pathways involved in protecting structure-prone DNA sequences from DSB formation and in repairing DSBs generated upon fork collapse at structure-prone DNA sequences. Furthermore, we will study how mismatch repair (MMR) proteins help preserve the integrity of structure-prone DNA sequences. Our studies will yield molecular insights into the mechanisms underlying the maintenance of the integrity of CFS and other structure-prone DNA sequences. These studies will also lay the groundwork for development of new targeted cancer treatment strategies.

主要研究者：吴晓华 项目摘要 研究保护常见脆弱部位和结构的机制- 倾向DNA序列 项目总结/摘要 常见脆性位点（CFS）是大的染色体区域，通常表现出缺口， 在复制应激时在中期染色体上断裂。结构倾向性AT富集序列 CFS-AT的存在有助于CFS不稳定性。除了CFS-AT，其他结构倾向 DNA序列，如G-四链体（G4），在人类基因组中也很丰富， 与癌症中的染色体重排断裂点有关。由于CFSs和许多 结构倾向性DNA序列，包括G4，是正常染色体结构的一部分，确实如此 重要的是要了解这些结构倾向的DNA序列的完整性是如何保持在 哺乳动物细胞在这项资助申请中，我们将使用基于EGFP的DSB修复报告基因， 研究潜在的机制，保护结构倾向的DNA序列存在于 CFS和G4。我们将研究染色质重塑在CFS维持中的作用， 解决DSB修复机制，特别是用于修复DSB产生的DNA二级 分叉后的结构崩溃。我们还将探讨相关途径的功能协调 在保护结构倾向DNA序列免于DSB形成和修复DSB产生中， 在结构倾向性DNA序列处发生分叉崩溃时。此外，我们将研究如何不匹配 修复（MMR）蛋白有助于保持结构倾向DNA序列的完整性。我们的研究 将从分子水平深入了解CFS完整性维持的机制 和其他结构倾向的DNA序列。这些研究还将为以下方面奠定基础： 开发新的靶向癌症治疗策略。