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The Role of DNA dynamics in damage recognition

DNA 动力学在损伤识别中的作用

基本信息

批准号：
BB/T008032/1
负责人：
Timothy Craggs
金额：
$ 64.28万
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FT008032%2F1
关键词：
Role DNA dynamics damage recognition

项目摘要

The ability of cells to faithfully replicate and transmit their genetic information (their DNA) is essential in all living organisms. The process requires accurately reproducing a sequence of billions of nucleotide units into two identical copies. In addition, natural cellular processes and environmental factors can result in damage to the DNA that must be repaired. Failing to precisely duplicate and/or repair the genetic material can result in diseases including cancer. During DNA replication, DNA structures deviating from the double helix are formed that must be processed by specialized enzymes to return the DNA to its normal double helical state. Another class of enzymes repair chemically damaged DNA. In this project we want understand how these different classes of enzymes recognize aberrant DNA within a vast sea of normal DNA.This is the very first step in the repair process, and as such is of central importance. Many people have looked at this process from the point of view of the proteins, but we will seek to discover if differences in the dynamics of the DNA are also important.Specifically, we will discover if changes in DNA flexibility could be one mechanism by which repair enzymes quickly locate their substrates. To do this, we will look at the conformations (shapes) of individual DNA molecules, one at a time (and so overcome any ensemble averaging). We will also implement a new method, X-ray scattering interferometry technique (that has not yet been used in the UK) which works by measuring the distances between tiny gold crystals attached to the DNAs. This measurement is so fast that it provides a snapshot of all the different shapes a DNA adopts in solution i.e. the un-averaged, conformational ensemble. We will compare these conformational ensembles for normal duplexes and a range of aberrant DNAs, to understand the role of flexibility in genome stability.In human cells, DNA is packed around proteins (histones), into particles called nucleosomes. In the last part of the project we will see if aberrant DNA structures pack differently to normal duplex DNAs, possibly leaving themselves more open for repair proteins to interact with.Our project will use cutting-edge experimental methods, combined with computer simulations to understand the role of conformational dynamics in aberrant DNA recognition.

细胞忠实地复制和传递其遗传信息（DNA）的能力在所有生物体中都是必不可少的。这个过程需要精确地将数十亿个核苷酸单位的序列复制成两个相同的副本。此外，自然细胞过程和环境因素可能导致DNA受损，必须修复。不能精确地复制和/或修复遗传物质会导致包括癌症在内的疾病。在DNA复制过程中，偏离双螺旋结构的DNA结构必须经过特殊的酶处理才能恢复到正常的双螺旋状态。另一类酶修复化学损伤的DNA。在这个项目中，我们想要了解这些不同种类的酶是如何在大量正常DNA中识别异常DNA的。这是修复过程的第一步，也是至关重要的一步。许多人已经从蛋白质的角度研究了这个过程，但我们将试图发现DNA动力学的差异是否也很重要。具体来说，我们将发现DNA灵活性的变化是否可能是修复酶快速定位其底物的一种机制。为了做到这一点，我们将观察单个DNA分子的构象（形状），一次一个（这样就克服了任何总体平均）。我们还将实施一种新的方法，x射线散射干涉测量技术（在英国尚未使用），该技术通过测量附着在dna上的微小金晶体之间的距离来工作。这种测量是如此之快，以至于它提供了一个DNA在溶液中所有不同形状的快照，即非平均的构象集合。我们将比较正常双链和一系列异常dna的这些构象集合，以了解灵活性在基因组稳定性中的作用。在人类细胞中，DNA被包裹在蛋白质（组蛋白）周围，形成称为核小体的颗粒。在项目的最后一部分，我们将看到异常的DNA结构是否与正常的双工DNA包装不同，这可能使它们更容易与修复蛋白相互作用。我们的项目将使用尖端的实验方法，结合计算机模拟来了解构象动力学在异常DNA识别中的作用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Making Precise and Accurate Single-Molecule FRET Measurements using the Open-Source smfBox.

使用开源 smfBox 进行精确且准确的单分子 FRET 测量。

DOI：
10.3791/62378
发表时间：
2021
期刊：
JoVE
影响因子：
0
作者：
Abdelhamid MAS
通讯作者：
Abdelhamid MAS

The Stringent Response Inhibits 70S Ribosome Formation in Staphylococcus aureus by Impeding GTPase-Ribosome Interactions.

DOI：
10.1128/mbio.02679-21
发表时间：
2021-12-21
期刊：
mBio
影响因子：
6.4
作者：
Bennison DJ;Nakamoto JA;Craggs TD;Milón P;Rafferty JB;Corrigan RM
通讯作者：
Corrigan RM

(p)ppGpp inhibits 70S ribosome formation in Staphylococcus aureus by impeding GTPase-ribosome interactions

DOI：
10.1101/2021.01.19.427108
发表时间：
2021-01
期刊：
bioRxiv
影响因子：
0
作者：
D. J. Bennison;J. A. Nakamoto;Timothy D. Craggs;P. Milón;J. Rafferty;R. Corrigan
通讯作者：
D. J. Bennison;J. A. Nakamoto;Timothy D. Craggs;P. Milón;J. Rafferty;R. Corrigan

CHARMM-DYES: Parameterization of Fluorescent Dyes for Use with the CHARMM Forcefield

CHARMM-DYES：用于 CHARMM 力场的荧光染料参数化