Mechanisms of DNA Homology-directed Genome Repair and Tumor Suppression

项目摘要 遗传学研究，首先在真核生物模型中进行，最近在哺乳动物中进行，已经揭示， 同源性指导的DNA修复（HDR）在DNA双链的消除中起着关键作用 断裂和保存应激或损伤的DNA复制叉。HDR依赖于肿瘤 抑制因子BRCA 1-BARD 1、BRCA 2和PALB 2，其中的突变引起乳腺、卵巢和其他肿瘤， 癌的了解这些肿瘤抑制因子如何帮助介导HDR以及它们如何影响HDR的进展 突变失活对基因组完整性的影响受到纯化的挑战的阻碍 用于机械研究。我们的研究团队已经克服了这一挑战， 使我们能够破译这些肿瘤抑制因子支持HDR的机制。在 与美国国家癌症研究所指定的梅斯癌症中心的一个不断壮大的研究团队合作， 位于圣安东尼奥的德克萨斯州健康科学中心，并与外部合作者合作， 结构生物学和单分子生物物理学，我们将剖析的基本机制， HDR的不同阶段，以具体提供关于上述肿瘤的作用的见解 其中，我们还将与癌症预防中心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。我们相信我们的 解读人类发展报告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.