Kinase-dependent control of DNA replication and repair as a drug target in Trypanosoma brucei

DNA复制和修复的激酶依赖性控制作为布氏锥虫的药物靶标

• 批准号: BB/K006495/1
• 负责人: Richard McCulloch
• 金额: $ 55.88万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK006495%2F1
• 关键词: Kinase; dependent; control; DNA; replication

The life of any living organism is dictated by the information contained in its genome, the genetic material that is contained within all cells and viruses. The propagation of an organism requires that the genome is copied, thereby generating offspring. This copying process is referred to as replication, and is a reaction that is carried out by specific proteins at a specific time during growth. The genome must also be protected from damage, which comes in many forms that can compromise the chemical composition of the genetic material. Protection is frequently due to reactions that repair damage that has already been inflicted, and these reactions are carried out, like replication, at specific times during growth. In fact, the two reactions can influence each other. The co-ordination of each reaction with growth is determined by a widely characterised set of enzymes, called protein kinases, which modify components of the cellular machineries that drive replication and repair. Trypanosomes are parasites that blight the health and economy of huge parts of the world and appear to have unconventional aspects of genome replication and repair. We wish to ask if we can identify the kinase enzymes that control these reactions, and thus understand if and how these reactions might be different from humans and other animals that are infected by the parasites. If we can identify these parasite protein kinases, we intend to try and find chemicals that will stop their activity and might then stop the growth of the parasites. If this is successful, we will have uncovered new strategies to treat the diseases caused by the parasites. These strategies will be robust because they target one of the most important aspects of the biology of any organism, and may be applicable to other parasites and infective organisms.

任何活着的有机体的生命是由其基因组中包含的信息决定的，基因组中包含的遗传物质包含在所有细胞和病毒中。生物体的繁殖需要复制基因组，从而产生后代。这种复制过程被称为复制，是特定蛋白质在生长过程中的特定时间进行的反应。基因组还必须受到保护，不受损害，损害形式多种多样，可能损害遗传物质的化学成分。保护通常是由于修复已经造成的损害的反应，这些反应在生长过程中的特定时间进行，比如复制。事实上，这两种反应可以相互影响。每种反应与生长的协调是由一组具有广泛特征的酶决定的，这种酶被称为蛋白激酶，它修改驱动复制和修复的细胞机器的组件。锥虫是一种寄生虫，它危害世界上大部分地区的健康和经济，似乎具有基因组复制和修复的非常规方面。我们想问，我们是否能确定控制这些反应的激活酶，从而了解这些反应是否以及如何与感染寄生虫的人类和其他动物不同。如果我们能确定这些寄生虫蛋白激酶，我们打算尝试寻找能够阻止它们活动的化学物质，然后可能阻止寄生虫的生长。如果这是成功的，我们将发现治疗寄生虫引起的疾病的新策略。这些策略将是强大的，因为它们针对任何生物体生物学最重要的方面之一，并可能适用于其他寄生虫和感染性生物体。

项目成果

The ATR kinase of Trypanosoma brucei links DNA damage signalling and monoallelic control of surface antigen gene expression during antigenic variation

• DOI: 10.1101/435198
• 发表时间: 2018-10
• 期刊: bioRxiv
• 作者: J. Black;K. Crouch;L. Lemgruber;C. Lapsley;N. Dickens;J. Mottram;R. McCulloch

Trypanosoma brucei ATR Links DNA Damage Signaling during Antigenic Variation with Regulation of RNA Polymerase I-Transcribed Surface Antigens

• DOI: 10.1016/j.celrep.2019.12.049
• 发表时间: 2020-01-21
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Black, Jennifer Ann;Crouch, Kathryn;McCulloch, Richard
• 通讯作者: McCulloch, Richard

Genome-wide mapping reveals conserved and diverged R-loop activities in the unusual genetic landscape of the African trypanosome genome

• DOI: 10.1101/357020
• 发表时间: 2018-06
• 期刊: Nucleic Acids Research
• 影响因子: 14.9
• 作者: E. Briggs;G. Hamilton;K. Crouch;C. Lapsley;R. McCulloch

Genome-wide mapping reveals conserved and diverged R-loop activities in the unusual genetic landscape of the African trypanosome genome.

• DOI: 10.1093/nar/gky928
• 发表时间: 2018-12-14
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Briggs E;Hamilton G;Crouch K;Lapsley C;McCulloch R
• 通讯作者: McCulloch R

Chromosomal copy number variation analysis by next generation sequencing confirms ploidy stability in Trypanosoma brucei subspecies.

• DOI: 10.1099/mgen.0.000223
• 发表时间: 2018-10
• 期刊: Microbial genomics
• 影响因子: 3.9
• 作者: Almeida LV;Coqueiro-Dos-Santos A;Rodriguez-Luiz GF;McCulloch R;Bartholomeu DC;Reis-Cunha JL
• 通讯作者: Reis-Cunha JL