Tracking and tracing complex DNA structures critical to human health

罗莎琳德富兰克林建立DNA原子结构的开创性工作，巩固了我们对“生命分子”的理解。然而，复杂基因组DNA的行为和功能也在很大程度上受其材料特性，即形状和构象的控制。这种复杂性影响酶的相互作用，细胞如何老化（从而导致人体老化），并且可能是癌症等病理学的重要因素。准确理解复杂DNA纳米结构中的形状和构象如何影响DNA相互作用的挑战从根本上受到现有工具的限制。该项目将应用我们最先进的单分子原子力显微镜（AFM）技术，首次探索复杂的DNA纳米结构在癌细胞复制过程中如何形成，以及抗癌治疗如何影响这些DNA纳米结构的结构和构象，为它们的作用机制提供新的见解。鉴于复制应激抑制剂作为治疗剂的出现，以及人们对作用于DNA以影响细胞行为的生物物理力的认识日益提高，该项目完全能够促进我们对癌症中复杂DNA结构的理解。通过了解这种复杂性，我们可以揭示细胞中DNA的行为方式，以及当事情出错时哪些因素在起作用，以及我们如何利用这种材料获得治疗效果。

Rosalind Franklin's pioneering work to establish the atomic structure of DNA has underpinned much of our understanding of the 'molecule of life'. However the behaviour and function of complex genomic DNA is also heavily governed by its material characteristics i.e. shape and conformation. This complexity affects enzyme interactions, how cells age (and therefore aging of the human body) and can be a significant factor in pathologies such as cancer. The challenge of understanding exactly how shape and conformation in complex DNA nanostructures influences DNA interactions is fundamentally limited by the tools available. This project will apply our cutting edge single-molecule Atomic Force Microscopy (AFM) techniques to explore for the first time how complex DNA nanostructures form during replication in cancerous cells, and how anti-cancer therapeutics affect the structure and conformation of these DNA nanostructures, providing new insight into their mechanism-of-action. Given the emergence of replication stress inhibitors as therapeutic agents, and the increasing awareness of the biophysical forces that act on DNA to influence cell behaviour, this project is perfectly positioned to progress our understanding of complex DNA structures in cancer. By understanding this complexity, we can shed new light on how DNA in the cell behaves, and what factors are at play when things go wrong and how we can exploit this material for therapeutic gain.