Genomic Instability at DNA Nicks

DNA 缺口处的基因组不稳定性

• 批准号: 9324162
• 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/9324162
• 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; Human; Immune checkpoint inhibitor; 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; experimental study; helicase; killings; malignant breast neoplasm; multicatalytic endopeptidase complex; neoplastic cell; new therapeutic target; prevent; public health relevance; repaired; 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切口处的基因组不稳定性我们的目标是了解DNA切口可以引发导致基因组不稳定性的事件的机制。切口是最常见的DNA损伤形式。人类细胞每天都会经历成千上万的缺口，来自活性氧，电离辐射，以及许多DNA修复途径的中间体。切口可以通过单链断裂修复途径有效且忠实地修复，并且它们尚未被视为对基因组稳定性的威胁。我们实验室最近的结果挑战了这一观点。我们已经证明，切口可以启动同源性定向修复（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（洛）。缺口处的HDR不同于双链断裂处的HDR。它与转录相关，并优先修复转录的DNA链。缺口处的HDR可以通过通常被典型HDR抑制的非常有效的替代途径进行，这表明替代HDR在缺乏典型HDR的肿瘤中是有活性的。我们建议通过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。确定进行和调节切口引发的HDR的因素和途径。目标2.确定细胞周期是否在缺口处调节替代HDR。目标3.确定缺口处的HDR如何与转录偶联。这项拟议的研究将使我们能够识别具有切口启动HDR风险的肿瘤，并最大限度地减少它们对切口的暴露。它将确定减少切口引发的基因组不稳定性的治疗靶点，以及激活基因组不稳定性以产生杀死细胞的DNA损伤的治疗靶点。