Understanding the activity and role of DarTG, a toxin:antitoxin system responsible for a novel DNA modification

了解 DarTG（一种负责新型 DNA 修饰的毒素：抗毒素系统）的活性和作用

• 批准号: BB/R007195/1
• 负责人: Ivan Ahel
• 金额: $ 82.98万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR007195%2F1
• 关键词: Understanding; activity; role; DarTG; toxin

DNA is essential for all life (except for certain viruses) as is the genetic blueprint which is necessary for heredity and how cells are made. DNA itself can be modified and it is known that these modifications (which usually are made of side chains containing a single atom of carbon) have critical effects on how cells develop, respond to stress, and survive. We have recently discovered that in bacteria certain stretches of DNA can be altered by a much more complex modification consisting of at least five carbon atoms. Critically, this complex modification is highly toxic to bacteria, although we do not exactly understand why. These complex modifications are added to and removed from DNA by proteins called enzymes which we have identified. We have also found that this modification happens in bacteria which are important causes of human disease such as tuberculosis (which still kills many people across the world), E. coli food poisoning, and a superbug which causes serious disease in people in hospitals. In this project, we will study how the complex DNA modification occurs by studying the enzymes acting on DNA at an atomic level, and find out how the modification is controlled and removed. This will give us the opportunity to understand the process in great detail, and to devise a series of experiments using the bacteria themselves. We will look at how this and a related DNA modification affect the behaviour of bacteria, including their ability to cause disease. In the future this work should provide us with all the information that, in the future, could allow us to interfere with these enzymes to make new antibiotics that are desperately needed to treat resistant bacteria.

DNA对所有生命都是必不可少的(除了某些病毒)，遗传蓝图也是必不可少的，这是遗传和细胞如何形成所必需的。DNA本身是可以修饰的，众所周知，这些修饰(通常由含有单个碳原子的侧链组成)对细胞如何发育、应对压力和生存具有关键影响。我们最近发现，在细菌中，DNA的某些片段可以通过至少由五个碳原子组成的更复杂的修饰来改变。关键是，这种复杂的修饰对细菌有很强的毒性，尽管我们并不确切地了解其中的原因。这些复杂的修饰是通过我们已经确定的称为酶的蛋白质添加到DNA上和从DNA中移除的。我们还发现，这种修饰发生在细菌中，这些细菌是人类疾病的重要原因，如结核病(目前仍导致世界各地许多人死亡)、大肠杆菌食物中毒，以及一种在医院导致严重疾病的超级细菌。在这个项目中，我们将通过在原子水平上研究作用于DNA的酶来研究复杂的DNA修饰是如何发生的，并找出修饰是如何控制和移除的。这将使我们有机会详细了解这一过程，并利用细菌本身设计一系列实验。我们将研究这一点和相关的DNA修饰如何影响细菌的行为，包括它们致病的能力。在未来，这项工作应该会为我们提供所有的信息，在未来，可以让我们干扰这些酶，以制造新的抗生素，这些抗生素是治疗耐药细菌迫切需要的。

项目成果

CARM1 regulates replication fork speed and stress response by stimulating PARP1.

• DOI: 10.1016/j.molcel.2020.12.010
• 发表时间: 2021-02-18
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Genois MM;Gagné JP;Yasuhara T;Jackson J;Saxena S;Langelier MF;Ahel I;Bedford MT;Pascal JM;Vindigni A;Poirier GG;Zou L
• 通讯作者: Zou L

Bridging of DNA breaks activates PARP2-HPF1 to modify chromatin.

• DOI: 10.1038/s41586-020-2725-7
• 发表时间: 2020-09
• 期刊: Nature
• 影响因子: 64.8
• 作者: Bilokapic S;Suskiewicz MJ;Ahel I;Halic M
• 通讯作者: Halic M

Serine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signalling.

• DOI: 10.1038/s41467-023-38793-y
• 发表时间: 2023-06-02
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Fontana, Pietro;Buch-Larsen, Sara C.;Suyari, Osamu;Smith, Rebecca;Suskiewicz, Marcin J.;Schutzenhofer, Kira;Ariza, Antonio;Rack, Johannes Gregor Matthias;Nielsen, Michael L.;Ahel, Ivan
• 通讯作者: Ahel, Ivan

ADP-ribosylation of DNA and RNA.

• DOI: 10.1016/j.dnarep.2021.103144
• 发表时间: 2021-09
• 期刊: DNA repair
• 影响因子: 3.8
• 作者: Groslambert J;Prokhorova E;Ahel I
• 通讯作者: Ahel I

Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice.

• DOI: 10.3390/cells10020368
• 发表时间: 2021-02-10
• 期刊: Cells
• 影响因子: 6
• 作者: Crawford K;Oliver PL;Agnew T;Hunn BHM;Ahel I
• 通讯作者: Ahel I