Ubiquitylation pathways controlling the end of chromosome replication

控制染色体复制末端的泛素化途径

• 批准号: MC_UU_00018/4
• 负责人: Karim Labib
• 金额: $ 350.53万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Intramural
• 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=MC_UU_00018%2F4
• 关键词: Ubiquitylation; pathways; controlling; end; chromosome

Our cells contain a molecular machine, known as the ‘replisome’, which makes a precise copy of each of chromosomes before the cell divides in two, so that both of the ‘daughter cells’ contain all of the genetic information that is needed for life. The replisome is very carefully controlled, so that cells only make one single copy of the genetic blueprint that is contained in the chromosomes. If this regulation goes wrong, the results can be lethal in the most extreme case, or else can promote genetic diseases such as cancer. There is much still to learn about the regulation of the replisome. We study how cells destroy the replisome after it has completed its job, by marking the replisome for destruction by a process known as ‘ubiquitylation’. We aim to identify the molecular machines that ubiquitylate the replisome and thus drive its destruction, and we also want to know how this dangerous process is controlled, so that it only happens at the right time. This represents a fundamental issue in cell biology, and is also likely to shed new light on our understanding of cancer development, and potentially might suggest new ideas for future cancer treatments.

我们的细胞内有一台分子机器，称为“复制体”，它在细胞分裂成两条染色体之前精确复制每条染色体，因此两个“子细胞”都包含了生命所需的所有遗传信息。复制体受到非常仔细的控制，因此细胞只复制一份包含在染色体中的基因蓝图。如果这一规定出错，在最极端的情况下，结果可能是致命的，否则可能会促进癌症等遗传病的发生。关于复制体的调控，还有很多东西需要了解。我们研究细胞如何在复制体完成其工作后将其摧毁，方法是将复制体标记为通过一种称为泛素化的过程进行破坏。我们的目标是识别使复制体泛素化并从而驱动其破坏的分子机器，我们还想知道这一危险过程是如何控制的，以便它只在正确的时间发生。这代表了细胞生物学中的一个基本问题，也可能为我们对癌症发展的理解提供新的线索，并可能为未来的癌症治疗提供新的想法。

项目成果

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp15 endoribonuclease.

• DOI: 10.1042/bcj20210199
• 发表时间: 2021-07-16
• 期刊: The Biochemical journal
• 作者: Canal B;Fujisawa R;McClure AW;Deegan TD;Wu M;Ulferts R;Weissmann F;Drury LS;Bertolin AP;Zeng J;Beale R;Howell M;Labib K;Diffley JFX
• 通讯作者: Diffley JFX

DONSON is required for CMG helicase assembly in the mammalian cell cycle.

在哺乳动物细胞周期中，DONSON是CMG解旋酶组装所必需的。

• DOI: 10.15252/embr.202357677
• 发表时间: 2023-11-06
• 期刊: EMBO REPORTS
• 影响因子: 7.7
• 作者: Evrin, Cecile;Alvarez, Vanesa;Ainsworth, Johanna;Fujisawa, Ryo;Alabert, Constance;Labib, Karim P. M.
• 通讯作者: Labib, Karim P. M.

Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp15 Endoribonuclease

通过筛选 Nsp15 核糖核酸内切酶小分子抑制剂来鉴定 SARS-CoV-2 抗病毒化合物

• DOI: 10.1101/2021.04.07.438811
• 发表时间: 2021
• 作者: Canal B

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase.

• DOI: 10.1042/bcj20210219
• 发表时间: 2021-07-16
• 期刊: The Biochemical journal
• 作者: Basu S;Mak T;Ulferts R;Wu M;Deegan T;Fujisawa R;Tan KW;Lim CT;Basier C;Canal B;Curran JF;Drury LS;McClure AW;Roberts EL;Weissmann F;Zeisner TU;Beale R;Cowling VH;Howell M;Labib K;Diffley JFX
• 通讯作者: Diffley JFX

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease.

• DOI: 10.1042/bcj20210198
• 发表时间: 2021-07-16
• 期刊: The Biochemical journal
• 作者: Canal B;McClure AW;Curran JF;Wu M;Ulferts R;Weissmann F;Zeng J;Bertolin AP;Milligan JC;Basu S;Drury LS;Deegan TD;Fujisawa R;Roberts EL;Basier C;Labib K;Beale R;Howell M;Diffley JFX
• 通讯作者: Diffley JFX