Mechanisms of DNA Homology-directed Genome Repair and Tumor Suppression

DNA同源引导的基因组修复和肿瘤抑制机制

• 批准号: 10013190
• 负责人: Patrick Sung
• 金额: $ 92.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10013190
• 关键词: BARD1 gene; BRCA1 gene; BRCA2 gene; Biology; Biophysics; Breast; Cancer Center; Cancer Diagnostics; Chemicals; Chromosomes; Counseling; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA replication fork; Etiology; Eukaryota; Foundations; Genetic study; Genome; Health Sciences; Knowledge; Malignant Neoplasms; Mammals; Mediating; Medical; Modeling; Mutation; Ovarian; Patients; Play; Positioning Attribute; Research; Research Institute; Role; Stress; Texas; Therapeutic; Tumor Suppression; Tumor Suppressor Proteins; Universities; acquired drug resistance; cancer prevention; drug discovery; drug response prediction; genome integrity; holistic approach; inhibitor/antagonist; innovation; insight; novel; preclinical study; preservation; repaired; single molecule; structural biology; tool

Project Summary Genetic studies, first done in model eukaryotes and more recently in mammals, have revealed that homology-directed DNA repair (HDR) plays a critical role in the elimination of DNA double-strand breaks and in the preservation of stressed or injured DNA replication forks. HDR is reliant on the tumor suppressors BRCA1-BARD1, BRCA2, and PALB2, mutations in which cause breast, ovarian, and other cancers. Progress in understanding how these tumor suppressors help mediate HDR and how their mutational inactivation impacts upon genome integrity has been hampered by the challenge of purifying them for mechanistic studies. Our research team has overcome this challenge, which uniquely positions us to decipher the mechanisms by which these tumor suppressors support HDR. In conjunction with a growing research team in the NCI-designated Mays Cancer Center at the University of Texas Health Science Center at San Antonio and with external collaborators who are leaders in structural biology and single-molecule biophysics, we will dissect the underlying mechanisms of different stages of HDR, to specifically furnish insights regarding the roles of the aforementioned tumor suppressors therein. We will also pursue chemical screens and synthesis with the Cancer Prevention and Research Institute of Texas (CPRIT)-supported Center for Innovative Drug Discovery to develop inhibitors of HDR to use as a chemical biology tool and for preclinical studies. We are confident that our holistic approach to deciphering HDR mechanisms will provide the foundation for developing targeted cancer diagnostics and therapeutics.

项目摘要 遗传研究首先是在模型真核生物中进行的，最近在哺乳动物中进行的遗传研究表明 同源指导的DNA修复（HDR）在消除DNA双链中起着至关重要的作用 断裂并保存压力或受伤的DNA复制叉。 HDR依赖于肿瘤 抑制器BRCA1-BARD1，BRCA2和PALB2，引起乳房，卵巢和其他的突变 癌症。了解这些肿瘤抑制器如何帮助介导HDR以及如何如何 纯化的挑战阻碍了突变失活对基因组完整性的影响 它们进行机械研究。我们的研究团队克服了这一挑战，这是独特的 定位我们将这些肿瘤抑制剂支持HDR的机制破译。在 与大学NCI指定的MAYS癌症中心不断发展的研究团队的结合 位于圣安东尼奥的德克萨斯健康科学中心，与外部合作者一起是领导者 结构生物学和单分子生物物理学，我们将剖析基本机制 HDR的不同阶段，专门提供有关上述肿瘤角色的见解 其中的抑制器。我们还将通过癌症预防进行化学筛选和合成 德克萨斯州研究所（CPRIT） - 支持的创新药物发现中心开发 HDR用作化学生物学工具和临床前研究的抑制剂。我们有信心我们的 解密HDR机制的整体方法将为开发目标提供基础 癌症诊断和治疗学。