Mechanisms of DNA Homology-directed Genome Repair and Tumor Suppression

项目概要 遗传研究首先在模型真核生物中进行，最近又在哺乳动物中进行，结果表明 同源定向 DNA 修复 (HDR) 在消除 DNA 双链中发挥着关键作用 断裂以及保存受压或受损的 DNA 复制叉。 HDR 依赖于肿瘤 BRCA1-BARD1、BRCA2 和 PALB2 抑制基因，这些突变会导致乳腺癌、卵巢癌和其他疾病 癌症。在了解这些肿瘤抑制因子如何帮助介导 HDR 以及它们如何发挥作用方面取得了进展 突变失活对基因组完整性的影响受到纯化挑战的阻碍 他们进行机械研究。我们的研究团队克服了这一挑战，这是独一无二的 使我们能够破译这些肿瘤抑制因子支持 HDR 的机制。在 与 NCI 指定的大学梅斯癌症中心不断壮大的研究团队合作 位于圣安东尼奥的德克萨斯健康科学中心以及在以下领域处于领先地位的外部合作者 结构生物学和单分子生物物理学，我们将剖析其潜在机制 HDR 的不同阶段，专门提供有关上述肿瘤作用的见解 其中的抑制器。我们还将与癌症预防一起进行化学筛选和合成 和德克萨斯研究所 (CPRIT) 支持的创新药物发现中心开发 HDR 抑制剂用作化学生物学工具和用于临床前研究。我们有信心我们的 破译 HDR 机制的整体方法将为制定有针对性的 癌症诊断和治疗。

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.