权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Licensing Transcription Activator Activity with Ubiquitin Time Clocks

使用泛素时钟许可转录激活剂活动

基本信息

批准号：
BB/L006219/1
负责人：
Steven Spoel
金额：
$ 59.54万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL006219%2F1
关键词：
Licensing Transcription Activator Activity Ubiquitin

项目摘要

Cells of complex higher organisms rely on information contained in their DNA genomes to provide instructions for development and how to respond to changes in their environment. The majority of information in the cell's genome is stored in genes that can be accessed by reading them, resulting in so-called gene expression. Gene expression is fine-tuned by the action of many different factors, amongst which activator proteins play a pivotal role. Activators exhibit potent activity that recruits all the other necessary factors for the expression of their target genes. They are therefore indispensable for accessing the information contained in genes but at the same time their strong activity poses a serious threat, as excessive gene expression can lead to genome instability and mutation. Accordingly, failure to correctly regulate the activity of activators often has catastrophic pathological consequences for an organism, including cancer cell formation, hormone imbalance, and either autoimmunity or low immune function. Despite the serious penalties associated with activator dysfunction, little is understood about how cells regulate their activity. Recently, data from our lab and others showed that many potent activators are unstable proteins because they are fused with chains of the small protein ubiquitin, a signal for activator degradation. From these data it has been hypothesized that cells provide activators with a limited license for activity and when this license expires the activator is degraded. While this is an attractive mechanism for keeping activators in check, the molecular identity of this license and the length of its validity remain elusive. Our latest genetic experiments suggest that we are now able to trap activators in their fully licensed states by mutating enzymes that potentially modify the length of ubiquitin chains fused to activators. Here we will investigate these enzymes in detail as they point to ubiquitin chain length being an adjustable time clock for activator activity. Using genetic, genomic, and biochemical tools we will identify all ubiquitin chain modifying enzymes involved in this process and assess their role in licensing activator activity. Unravelling the mechanisms by which activator activity is fine-tuned will provide deep insight into how higher organisms -from humans to plants- regulate access to information contained within their genomes. Such fundamental knowledge offers the foundation for designing new medicines or therapies to tackle a range of human diseases and for modernizing agriculture with novel crop protection strategies.

复杂高等生物的细胞依赖于DNA基因组中包含的信息来提供发育指示以及如何应对环境变化。细胞基因组中的大部分信息存储在基因中，通过阅读可以访问这些基因，从而导致所谓的基因表达。基因表达是由许多不同因素的作用，其中激活蛋白发挥关键作用微调。激活剂表现出强有力的活性，募集所有其他必要的因子来表达其靶基因。因此，它们对于获取基因中所含的信息是不可或缺的，但与此同时，它们的强烈活性构成了严重威胁，因为过度的基因表达可能导致基因组不稳定和突变。因此，不能正确调节激活剂的活性通常对生物体具有灾难性的病理后果，包括癌细胞形成、激素失衡以及自身免疫或免疫功能低下。尽管与激活剂功能障碍相关的严重惩罚，但对细胞如何调节其活性知之甚少。最近，来自我们实验室和其他实验室的数据表明，许多有效的激活剂是不稳定的蛋白质，因为它们与小蛋白泛素的链融合，泛素是激活剂降解的信号。根据这些数据，已经假设细胞为激活剂提供有限的活性许可，并且当该许可到期时，激活剂被降级。虽然这是一个有吸引力的机制，以保持激活剂在检查，分子身份的这种许可证和其有效期的长度仍然难以捉摸。我们最新的遗传实验表明，我们现在能够通过突变酶来捕获处于完全许可状态的激活剂，这些酶可能会改变与激活剂融合的泛素链的长度。在这里，我们将详细研究这些酶，因为它们指出泛素链长度是激活剂活性的可调节时钟。使用遗传学，基因组学和生物化学的工具，我们将确定所有的泛素链修饰酶参与这一过程，并评估其在许可激活剂活性的作用。解开激活剂活性微调的机制将深入了解高等生物-从人类到植物-如何调节其基因组中包含的信息。这些基础知识为设计新的药物或疗法以应对一系列人类疾病以及通过新的作物保护战略实现农业现代化奠定了基础。