Helicase regulation during homologous recombination

同源重组过程中解旋酶的调节

• 批准号: 10556346
• 负责人: Eric C Greene
• 金额: --
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556346
• 关键词: Address; Affect; Aging; BARD1 gene; BRCA1 gene; Biochemical; Biomedical Research; Cancer Biology; Cells; Chromosomal Rearrangement; Chromosomes; Clinical; Complex; DNA; DNA Double Strand Break; DNA Repair Pathway; DNA biosynthesis; DNA metabolism; DNA replication fork; DNA strand break; Defect; Dependence; Disease; Eukaryota; Eukaryotic Cell; Exhibits; Funding; Future; Genetic Diseases; Genetic Recombination; Genome Stability; Goals; Health; Homologous Gene; Human; Human Biology; Human Genome; Hydrolysis; Individual; Link; Malignant Neoplasms; Mediating; Microscopy; Molecular; Molecular Motors; Mutation; Nucleic Acids; Nucleoproteins; Optics; Outcome; Pathway interactions; Patients; Play; Predisposition; Premature aging syndrome; Process; Property; Proteins; RAD52 gene; RECQL5 gene; Reaction; Recovery; Regulation; Research; Role; Saccharomyces cerevisiae; Single-Stranded DNA; Source; Specificity; Syndrome; Testing; Visualization; Work; cancer cell; cancer therapy; cofactor; design; genetic information; genetic regulatory protein; genome integrity; helicase; homologous recombination; human disease; inhibitor; insight; new technology; nucleic acid metabolism; nucleoside triphosphate; p53-binding protein 1; paralogous gene; presynaptic; prevent; protein complex; recombinase; repaired; single molecule; targeted treatment; therapeutic development; time use; tool

Project Summary Our chromosomes are continually bombarded with a variety of insults, resulting in damage that must be repaired. By necessity, cells have evolved mechanisms to detect and repair broken strands of DNA, thereby preventing loss of important genetic information. Double-stranded DNA breaks (DSBs) are a type of damage that led to particularly disastrous outcomes. If not corrected, DSBs can lead to gross chromosomal rearrangements, which are the hallmark of all forms of cancer. Indeed, defects in HR- related proteins are associated with several severe genetic diseases. Patients with these diseases often exhibit a strong predisposition for developing cancers due to a loss of genome integrity. Surprisingly, DNA replication is the primary source of DSBs, and as a consequence rapidly growing cells are especially dependent upon homologous DNA recombination for survival. This dependence upon homologous recombination for the survival of rapidly growing cells highlights the potential for using recombination inhibitors as highly selective cancer therapies. To fully exploit the clinical potential of homologous recombination inhibitors it will be essential that we more fully understand the detail molecular underpinnings of recombination and the proteins that are involved in regulating and controlling this process. To help better understand the molecular basis of homologous DNA recombination we have developed powerful new experimental platforms that allow us to directly visualize hundreds of individual DNA molecules at the single molecule level. We are utilizing these unique research tools to probe the fundamental basis for protein-nucleic acid interactions, with emphasis placed upon understanding reactions relevant to human biology and disease. Here we will assess how ATP-dependent helicases can exert “antirecombinase” activities and regulate homologous recombination by dismantling key recombination intermediates. We will accomplish this goal by directly visualizing these processes in real- time using optical microscopy. We will analyze factors that influence antirecombinase function and specificity, we will determine precisely how antirecombinases dismantle recombination intermediates, and we will seek to establish an understanding of common themes conserved among different eukaryotic antirecombinases, as well as define the unique attributes of those proteins that are of particular importance to human health. We will seek to determine detailed molecular information related to these questions, and part of the significance of this project lies in the depth of the answers we strive to obtain.

项目概要 我们的染色体不断受到各种侮辱的轰炸，造成必须予以修复的损害 细胞必然会进化出检测和修复断裂DNA链的机制， 从而防止丢失重要的遗传信息。双链 DNA 断裂 (DSB) 是一种类型。 如果不加以纠正，DSB 可能会导致严重的后果。 染色体重排是所有形式癌症的标志，事实上，HR-缺陷。 相关蛋白质通常与患有这些疾病的患者有关。 令人惊讶的是，由于基因组完整性的丧失，它们表现出强烈的罹患癌症的倾向。 DNA 复制是 DSB 的主要来源，因此快速生长的细胞尤其 生存依赖于同源DNA重组。 重组促进快速生长细胞的存活凸显了利用重组的潜力 抑制剂作为高度选择性的癌症疗法，充分发挥同源物的临床潜力。 重组抑制剂 我们必须更全面地了解分子细节 重组的基础以及参与调节和控制重组的蛋白质 过程。 为了帮助更好地理解同源 DNA 重组的分子基础，我们开发了 强大的新实验平台使我们能够直接可视化数百个个体 DNA 我们正在利用这些独特的研究工具来探索单分子水平的分子。 蛋白质-核酸相互作用的基本基础，重点是理解 在这里，我们将评估 ATP 依赖性解旋酶如何发挥作用。 发挥“抗重组酶”活性，通过拆解关键调控同源重组 我们将通过直接可视化这些过程来实现这一目标。 我们将使用光学显微镜分析影响抗重组酶功能的因素和时间。 特异性，我们将精确确定抗重组酶如何拆除重组中间体， 我们将寻求建立对不同真核生物之间保守的共同主题的理解 抗重组酶，以及定义那些特别重要的蛋白质的独特属性 我们将寻求确定与这些问题相关的详细分子信息，以及 这个项目的部分意义在于我们努力获得答案的深度。