Determining the susceptibility of nucleic acids to damage as a function of structure

“这个项目是为了研究核酸（DNA和RNA）的结构与它们对损伤的敏感性之间的关系。核酸的化学修饰可以对细胞活力和功能产生深远的影响。DNA可以被许多化学物质破坏，包括活性氧（ROS）。这导致基因组内的突变，这可能导致许多不同的疾病，包括癌症，并且是包括额颞叶痴呆症在内的几种神经退行性疾病的标志。在阿尔茨海默病中，铁等金属会通过芬顿化学作用增加核酸遭受的损伤量。然而，DNA和RNA可以采用各种各样的结构，这取决于序列和化学环境。因此，该项目旨在通过研究晶体中的损伤过程来确定损伤热点，从而研究核酸结构与首选损伤位点之间的关系。这可能导致预测生物相关序列中最有可能发生损伤的位置的能力。在这个项目中，您将生长核酸晶体并开发晶体状态下的化学修饰方法。您将使用各种最先进的技术，包括单晶X射线衍射（具有可变水合和原位筛选）、同步辐射圆二色性和UV/可见光吸收以研究晶体和溶液状态中的损伤，以深入了解核酸的结构如何引导损伤。成功的申请人将作为团队的一员工作，并将有机会该项目由阅读大学和工程与物理科学研究理事会（EPSRC）支持。

"This project is to examine the relationship between the structure of nucleic acids (DNA and RNA) and their susceptibility to damage. Chemical modification of nucleic acids can have a profound effect on cell viability and function. DNA can be damaged by a number of chemical species including reactive oxygen species (ROS). This causes mutation within the genome which can lead to a number of different diseases, including cancer, and is a hallmark of several neurodegenerative diseases including frontotemporal dementia. In Alzheimer's disease, metals such as iron can increase the amount of damage suffered by nucleic acids through Fenton chemistry. However, DNA and RNA can adopt a wide variety of structures depending on both the sequence and chemical environment. The project is therefore to examine the relationship between nucleic acid structure and the preferred sites of damage, by studying the damage process in crystals to identify damage hotspots. This could lead to the ability to predict where damage is most likely to occur in biologically relevant sequences. In this project you will grow crystals of nucleic acids and develop methods for chemical modification in the crystal state. You will use a variety of state-of-the-art techniques including single-crystal X-ray diffraction (with both variable hydration and in situ screening), synchrotron radiation circular dichroism and UV/visible absorption to study damage in the crystal and solution state, to gain a thorough understanding of how the structure of the nucleic acid directs damage.The successful applicant will work as a part of a team and will have the opportunity to work at Diamond Light Source during the project, which is supported by the University of Reading and the Engineering and Physical Sciences Research Council (EPSRC).