Genomic Instability at DNA Nicks

DNA 缺口处的基因组不稳定性

• 批准号: 9111836
• 负责人: Nancy Maizels
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-09 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111836
• 关键词: BRCA1 gene; BRCA2 gene; Cell Cycle; Cell Cycle Regulation; Cell Cycle Stage; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; DNA; DNA Damage; DNA Polymerase II; DNA Repair Pathway; DNA lesion; Dependence; Development; Down-Regulation; Drug Targeting; Endonuclease I; Enzyme Stability; Event; Exposure to; Frequencies; G1 Phase; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Goals; Guide RNA; Health; Human; Ionizing radiation; Laboratories; Lead; Loss of Heterozygosity; Malignant neoplasm of ovary; Molecular Analysis; Mutation; Normal Cell; Nuclear; PTEN gene; Pathway interactions; Pharmaceutical Preparations; RECQL5 gene; RNA; Reactive Oxygen Species; Research; Risk; S Phase; Signal Transduction; Single Strand Break Repair; Site; Solid Neoplasm; Source; Testing; Therapeutic; cancer cell; cell killing; chromatin immunoprecipitation; experience; helicase; inhibitor/antagonist; killings; malignant breast neoplasm; multicatalytic endopeptidase complex; neoplastic cell; new therapeutic target; prevent; repaired; research study; response; targeted treatment; therapy development; tool; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Genomic Instability at DNA Nicks Our goal is to understand the mechanisms by which DNA nicks can initiate events that lead to genomic instability. Nicks are the most common form of DNA damage. Human cells experience tens of thousands of nicks each day, from reactive oxygen species, ionizing radiation, and as intermediates in many pathways of DNA repair. Nicks can be efficiently and faithfully repaired by the single strand break repair pathway, and they have not been viewed as a threat to genomic stability. Recent results from our laboratory challenge that view. We have shown that nicks can initiate homology-directed repair (HDR), a source of two forms of genomic instability common in tumors, copy number alteration (CNA) and loss of heterozygosity (LOH). HDR at nicks is distinct from HDR at double strand breaks. It is associated with transcription and preferentially repairs the transcribed DNA strand. HDR at nicks can proceed via a very efficient alternative pathway that is normally suppressed by canonical HDR, suggesting that alternative HDR is active in tumors that are deficient in canonical HDR. We propose to define the mechanisms by which nicks initiate HDR and genomic instability, by carrying out the following three specific Aims: Aim 1. To define the factors and pathways that carry out and regulate nick-initiated HDR. Aim 2. To establish whether the cell cycle regulates alternative HDR at nicks. Aim 3. To determine how HDR at nicks is coupled to transcription. The proposed research will enable us to identify tumors at risk for nick-initiated HDR, and minimize their exposure to nicks. It will identify targets for therapies that diminish nick-initiated genomic instability, as well as targets for therapies that activate genomic instability to create DNA damage that kills cells.

描述（由申请人提供）：DNA 切口的基因组不稳定性 我们的目标是了解 DNA 切口引发导致基因组不稳定的事件的机制。刻痕是最常见的 DNA 损伤形式。人类细胞每天都会经历数万个切口，这些切口来自活性氧、电离辐射以及许多 DNA 修复途径的中间体。缺口可以通过单链断裂修复途径有效且忠实地修复，并且它们并未被视为对基因组稳定性的威胁。我们实验室的最新结果挑战了这一观点。我们已经证明，切口可以启动同源定向修复（HDR），这是肿瘤中常见的两种形式的基因组不稳定性的来源，即拷贝数改变（CNA）和杂合性丢失（LOH）。切口处的 HDR 与双链断裂处的 HDR 不同。它与转录相关并优先修复转录的 DNA 链。缺口处的 HDR 可以通过一种非常有效的替代途径进行，该途径通常被典型 HDR 抑制，这表明替代 HDR 在典型 HDR 缺陷的肿瘤中活跃。我们建议通过实现以下三个具体目标来定义切口启动 HDR 和基因组不稳定性的机制： 目标 1. 定义执行和调节切口启动 HDR 的因素和途径。目标 2. 确定细胞周期是否调节缺口处的替代 HDR。目标 3. 确定缺口处的 HDR 如何与转录结合。拟议的研究将使我们能够识别有切口引发 HDR 风险的肿瘤，并最大限度地减少它们与切口的接触。它将确定减少切口引发的基因组不稳定性的治疗靶标，以及激活基因组不稳定性以产生杀死细胞的 DNA 损伤的治疗靶标。