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.

项目总结