Understanding the mechanobiology of DNA-protein interactions at the single-molecule level

了解单分子水平 DNA-蛋白质相互作用的力学生物学

• 批准号: 2741120
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2741120
• 关键词: Understanding; mechanobiology; DNA; protein; interactions

DNA-protein interactions underpin essential cellular processes such as DNA replication, transcription, and repair, and proteins involved in these processes are targeted in a variety of cancer therapies. Many structures of damaged DNA-protein complexes reveal stark bends in the DNA substrate, suggesting that proteins may exert force on the DNA to bend it during recognition of the damage site, or for catalytic enhancement of the repair. Two such proteins are FEN1 (essential for NER and Okasaki fragment processing) and XPA (essential to NER). Here we will develop novel instrumentation to investigate how force modulates the DNA-protein interactions involved in DNA repair at a fundamental level, and establish high-throughput screening methods which mimic physiological forces on DNA substrates (which naturally arise in cells due to transcription and packaging) to improve hit identification for repair inhibitors.

DNA-蛋白质相互作用是DNA复制、转录和修复等基本细胞过程的基础，参与这些过程的蛋白质是各种癌症治疗的靶点。许多受损的DNA-蛋白质复合物的结构在DNA底物中显示出明显的弯曲，这表明蛋白质可能在识别损伤位点的过程中对DNA施加力以使其弯曲，或者用于修复的催化增强。两种这样的蛋白质是FEN 1（NER和Okasaki片段加工所必需的）和XPA（NER所必需的）。在这里，我们将开发新的仪器来研究力如何在基本水平上调节DNA修复中涉及的DNA-蛋白质相互作用，并建立高通量筛选方法，模拟DNA底物上的生理力（由于转录和包装而在细胞中自然产生），以提高修复抑制剂的命中识别。