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

基本信息

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
项目类别：
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

项目摘要

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.

首席研究员：吴晓华项目概要研究保护常见脆弱地点和结构的机制易发生的DNA序列项目概要/摘要常见脆弱位点 (CFS) 是大的染色体区域，经常表现出间隙和复制应激时中期染色体断裂。结构倾向丰富的 AT 序列 CFS 中的存在 (CFS-AT) 会导致 CFS 不稳定。除了 CFS-AT 之外，还有其他结构倾向 DNA 序列，例如 G-四链体 (G4)，在人类基因组中也很丰富，并且与癌症中的染色体重排断点有关。由于 CFS 和许多易于结构的 DNA 序列，包括 G4，是正常染色体结构的一部分，它是了解这些易于结构的 DNA 序列的完整性如何在哺乳动物细胞。在此拨款申请中，我们将使用基于 EGFP 的 DSB 修复报告器研究保护易结构 DNA 序列的潜在机制 CFS 和 G4。我们将研究染色质重塑在维持 CFS 和解决 DSB 修复机制，专门用于修复 DNA 次级产生的 DSB 叉子塌陷时的结构。我们还将探索相关途径的功能协调保护易于结构的 DNA 序列免受 DSB 形成以及修复生成的 DSB 当叉在易于结构的 DNA 序列处塌陷时。此外，我们将研究失配如何修复 (MMR) 蛋白有助于保持易出现结构的 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见解和其他易于结构的 DNA 序列。这些研究也将为开发新的靶向癌症治疗策略。