The multifaceted roles of PLK4

PLK4 的多方面作用

• 批准号: RGPIN-2015-05947
• 负责人: Hudson, John
• 金额: $ 2.19万
• 依托单位: University of Windsor
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=654047
• 关键词: multifaceted; roles; PLK4

Years of carefully planned and carried out experiments has determined that the protein called Polo like kinase 4 (PLK4), is a major regulator of centrosome duplication. Centrosomes are small organelles, which are involved in ensuring that the genetic information in cells is passed on equally when a cell divides. PLK4 is a member of a group of proteins known as kinases. These proteins modify the structure and thereby the function or activity of proteins that they interact with. We and others have focused on establishing that alterations of PLK4 levels, either due to an increase or a decrease, have a detrimental effect on cells. PLK4 plays an important role during development, as mouse lacking one allele of plk4 (resulting in lower levels) arrest at day 7.5 of embryonic development. Thus the next question has become what are PLK4 interacting partners and which pathways are affected by changes in PLK4 levels? Data from our NSERC program has characterized interactions between PLK4 and proteins that function in playing a role in how a cell responds to DNA damage. Our recent results in frog embryos indicate a major and conserved role for PLK4 during embryonic development. We also have evidence that PLK4 function is regulated at an epigenetic level and that it may play a role in epigenetic regulation itself. Epigenetics encompasses heritable changes that are not caused by changes in the DNA sequence. Specifically, we were the first to find that PLK4 levels are controlled by promoter methylation, an epigenetic mechanism. We have also found that PLK4 interacts with proteins involved in epigenetic regulation. In the current proposal we will be characterizing PLK4 interactions at the protein level and also addressing the exciting possibility of identifying novel PLK4 interacting partners. Our goal and focus throughout this research program is to delineate the function(s) of PLK4 during embryonic development, epigenetic regulation and the response to DNA damage. ******Hypothesis:***PLK4 plays unique roles in epigenetic regulation, in DNA damage pathways and during development.******Short-term objectives:***I. Determine whether PLK4 is an essential component of epigenetic regulation and/or the DNA damage response;***II. Determine the role of PLK4 during lens placode formation and somitogenesis;***III. To further understand the function of PLK4, we will use a novel approach to identify PLK4 interacting partners.******Long term objective:***To gain a more complete understanding of the roles that PLK4, a Ser/Thr kinase, plays in the cell.******Our data has revealed novel areas for PLK4 function. This research program seeks to resolve the molecular complexities and consequences associated with proper PLK4 function; data which is essential for the understanding of regulatory mechanisms in normally functioning cells. **

多年来精心计划和进行的实验已经确定，称为波罗样激酶4（PLK 4）的蛋白质是中心体复制的主要调节因子。中心体是一种小的细胞器，当细胞分裂时，它参与确保细胞中的遗传信息平等地传递。PLK 4是一组称为激酶的蛋白质的成员。这些蛋白质改变结构，从而改变与它们相互作用的蛋白质的功能或活性。我们和其他人一直致力于确定PLK 4水平的改变，无论是由于增加还是减少，都对细胞产生不利影响。PLK 4在发育过程中起重要作用，因为缺乏plk 4的一个等位基因的小鼠（导致较低水平）在胚胎发育的第7.5天停止。因此，下一个问题已经成为什么是PLK 4相互作用的伙伴，哪些途径受到PLK 4水平变化的影响？来自NSERC项目的数据表征了PLK 4和蛋白质之间的相互作用，这些蛋白质在细胞如何响应DNA损伤中发挥作用。我们最近在青蛙胚胎中的研究结果表明PLK 4在胚胎发育过程中的主要和保守的作用。我们也有证据表明PLK 4的功能在表观遗传水平上受到调节，并且它可能在表观遗传调节本身中发挥作用。表观遗传学包括不是由DNA序列变化引起的可遗传变化。具体来说，我们是第一个发现PLK 4水平受启动子甲基化控制的人，这是一种表观遗传机制。我们还发现PLK 4与参与表观遗传调控的蛋白质相互作用。在目前的提案中，我们将在蛋白质水平上表征PLK 4相互作用，并解决识别新型PLK 4相互作用伴侣的令人兴奋的可能性。我们的目标和重点在整个研究计划是描绘PLK 4在胚胎发育，表观遗传调控和DNA损伤的反应中的功能。** 假设：* PLK 4在表观遗传调控、DNA损伤途径和发育过程中发挥独特作用。短期目标：* 确定PLK 4是否是表观遗传调控和/或DNA损伤反应的重要组成部分;*II.确定PLK 4在透镜基板形成和体节发生期间的作用;*III.为了进一步了解PLK 4的功能，我们将使用一种新的方法来鉴定PLK 4相互作用的伴侣。长期目标：* 更全面地了解PLK 4（一种Ser/Thr激酶）在细胞中的作用。**我们的数据揭示了PLK 4功能的新领域。该研究项目旨在解决与PLK 4功能相关的分子复杂性和后果;这些数据对于理解正常功能细胞中的调控机制至关重要。**