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.

主要调查者：吴晓华 项目摘要 研究保护常见脆弱部位和结构的潜在机制- 易感染的DNA序列 项目摘要/摘要 常见的脆性部位(CFS)是大的染色体区域，通常表现出缺口和 复制胁迫下中期染色体的断裂。富含AT的富含结构序列 目前在CFSS(CFS-ATS)是导致CFS不稳定的原因。除了CFS-ATS，其他结构倾向于 DNA序列，如G-四链(G4S)，在人类基因组中也很丰富，而且 与癌症中的染色体重排断裂点有关。因为CFS和许多 易于结构的DNA序列，包括G4S，是正常染色体结构的一部分，它是 了解这些易于结构的DNA序列的完整性是如何在 哺乳动物细胞。在这次拨款申请中，我们将使用基于EGFP的DSB修复记者来 研究保护具有结构倾向的DNA序列的潜在机制 CFSS和G4S。我们将研究染色质重塑在CFSS和 介绍专门用于修复在DNA次要位置产生的DSB的DSB修复机制 叉子上的建筑物倒塌。我们还将探索所涉及的通路的功能协调 在保护易于结构的DNA序列免受DSB形成和修复产生的DSB方面 在易于结构的DNA序列分叉坍塌时。此外，我们还将研究错配如何 修复(MMR)蛋白有助于保持易于结构的DNA序列的完整性。我们的研究 将产生对维持CFS完整性的潜在机制的分子洞察 和其他易于结构的DNA序列。这些研究还将为 开发新的有针对性的癌症治疗策略。