Mechanisms of DNA Homology-directed Genome Repair and Tumor Suppression

项目摘要 最先在模型真核生物中进行的遗传学研究，最近在哺乳动物中进行的研究表明， 同源定向DNA修复(HDR)在消除DNA双链中起着关键作用 断裂和保存受压力或损伤的DNA复制叉。HDR依赖于肿瘤 抑制子BRCA1-BARD1、BRCA2和PALB2，其中的突变导致乳房、卵巢和其他 癌症。了解这些肿瘤抑制因子如何帮助介导HDR以及它们的 突变失活对基因组完整性的影响已受到提纯挑战的阻碍 他们进行机械学研究。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……里面 与NCI指定的大学梅斯癌症中心不断壮大的研究团队合作 在圣安东尼奥的德克萨斯健康科学中心与外部合作者合作，他们是 结构生物学和单分子生物物理学，我们将剖析其潜在的机制 HDR的不同阶段，以具体提供关于上述肿瘤的作用的见解 其中的抑制者。我们还将与癌症预防一起进行化学筛选和合成 和德克萨斯研究院(CPRIT)支持的创新药物发现中心将发展 HDR的抑制剂，用作化学生物学工具和临床前研究。我们相信，我们的 破译人类发展报告机制的整体方法将为制定有针对性的 癌症诊断和治疗学。

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.