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Defining the contributions of BRCA1, BRCA2, and RAD52 to genome stability

定义 BRCA1、BRCA2 和 RAD52 对基因组稳定性的贡献

基本信息

批准号：
9883062
负责人：
Eric C Greene
金额：
$ 41.09万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-11 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9883062
关键词：
Address Affect Aging Antineoplastic Agents BARD1 gene BRCA1 Protein BRCA1 gene BRCA2 Mutation BRCA2 gene Binding Biological Assay Cells Characteristics Chromosomal Rearrangement Chromosomes Clinical Complex DNA DNA Double Strand Break DNA Repair DNA Repair Pathway DNA Sequence DNA biosynthesis DNA replication fork Defect Dependence Development Disease Event Exhibits Filament Future Genetic Diseases Genetic Recombination Genome Stability Goals Hereditary Breast and Ovarian Cancer Syndrome Human Human Biology Human Genome Individual Lead Macromolecular Complexes Malignant Neoplasms Mediating Microscopy Molecular Mutate Normal Cell Nucleic Acids Nucleoproteins Optics Outcome Pathway interactions Patients Play Predisposition Process Property Proteins RAD52 gene Reaction Regulation Repair Complex Research Resistance Role Single-Stranded DNA Source Syndrome Time Transact Tumor Suppression Tumor Suppressor Proteins Work anti-cancer therapeutic anticancer research base cancer cell cancer therapy chemotherapy defined contribution experimental study genetic information genome integrity homologous recombination human DNA human disease human imaging inhibitor/antagonist insight malignant breast neoplasm presynaptic prevent protein complex repaired single molecule spatiotemporal therapeutic target time use tool

项目摘要

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 can result in 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 anti-cancer therapies. To exploit the clinical potential of homologous recombination inhibitors it will be essential that we more fully understand the molecular underpinnings of the proteins that are involved in regulating and controlling recombination. 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. We have used these assays to study human RAD51, which binds to single- stranded DNA forming a key recombination intermediate called the presynaptic complex. Here, we will assess how complexes containing the tumor suppressor protein complexes BRCA1-BARD1, BRCA2- DSS1, and PALB2 promote homologous recombination by regulating the activities of the RAD51 presynaptic complex. We will also examine how the protein RAD52, which newly recognized as an important target for anti-cancer drugs, interacts with RAD51, BRCA1-BARD1, BRCA2-DSS1, and PALB2. We will also study the protein RADX, which is emerging as a key player in genome integrity which functions to downregulate RAD51 activity. We will accomplish these goals by directly visualizing these processes in real-time using optical microscopy. These studies offer the potential for significant new insights into how BRCA1-BARD1, BRCA2-DSS1, PALB2 and RAD52 regulate homologous recombination and support human genome integrity.

项目总结