Can histone code-like 'switches' govern the multi-functionality of RNA-binding proteins?

构成我们细胞的蛋白质是由作为遗传蓝图的基因编码的。储存在基因中的信息被表达或解码，通过一个称为基因表达的多步骤过程来产生蛋白质。在这个过程中，DNA中的基因首先被转换(转录)为信使核糖核酸，作为制造蛋白质的模板。后一步称为信使核糖核酸翻译。为了正常运作，细胞和生物体需要在正确的时间、地点和正确的数量制造蛋白质。因此，对信使核糖核酸的翻译和寿命(即信使核糖核酸的使用和可获得性)进行仔细管理是至关重要的，控制不当会导致多种疾病，包括癌症、新陈代谢、神经和生殖障碍。调控翻译对需要有效合成特定蛋白质的工业过程也是至关重要的。对mRNA的加工、水平、利用(翻译)和破坏的细胞监测统称为“转录后控制”，因为它们发生在mRNA转录后，并由mRNA结合蛋白(RNA-Bps)执行。人类细胞可以表达&gt；1000RNA-bps，有趣的是，其中许多细胞在转录后控制过程中执行多种无关的功能，即它们是多功能的。然而，协调和监管多功能的方式只在少数情况下被理解。这在我们的知识中留下了一个至关重要的缺口，因为了解RNA-BP的协调对于描述转录后控制过程以及理解它们失败的原因以及如何将它们用于治疗或生物技术目的至关重要。我们最近揭示了许多RNA-BP在蛋白质的同一位置受到两种不同形式的化学修饰。这些修饰称为乙酰化和甲基化，不能同时在蛋白质的同一位置发生，这意味着RNA-BP可以以三种状态存在：未修饰、乙酰化或甲基化，每种修饰状态的不同化学性质可能赋予蛋白质改变功能或改变其与其他蛋白质相互作用的能力。令人着迷的是，这些修饰的特点是它们对称为组蛋白的蛋白质具有很好的功能，组蛋白有助于包装和调节细胞核中的细胞DNA，众所周知，它们在细胞核中的作用就像开关一样，实现不同的组蛋白功能。然而，这种开关以前从未在RNA-BP中被描述过，我们假设我们已经发现了一种新的RNA-BP的调节机制，可以解释它们的多功能是如何协调的。我们的目标是使用一个特性良好的多功能RNA-BP来验证这一假说，这种RNA-BP被称为Poly(A)结合蛋白(PABP)1，它的失调会影响生育、新陈代谢和学习/记忆等生理过程。我们已经在PABP1中发现了一个乙酰化/甲基化开关，该开关位于蛋白质内的一个位置，对于它与许多其他蛋白质的相互作用至关重要，这些蛋白质是PABP1各种功能所必需的。我们将测试开关调节特定PABP1伙伴蛋白结合的能力，并测试乙酰化或甲基化对PABP1转录后控制功能的影响。我们还将找出哪些细胞酶调节PABP1开关，以及在什么细胞环境下(例如，健康生长的细胞或不健康的细胞)。通过开展这项研究，我们的目标是揭示通过乙酰化/甲基化开关对RNA-Bps的调节，从而揭示转录后控制，并开辟一个新的研究领域，类似于现在熟知的通过组蛋白中类似开关来控制转录的领域。在这样做的过程中，我们将增加对调控基因表达的关键机制的理解，以确保体内细胞的正常功能和健康。

The proteins that make up our cells are encoded by genes that serve as a genetic blueprint. The information stored in genes is expressed, or decoded, to produce proteins by a multi-step process known as gene expression. In this process, the genes within DNA are first converted (transcription) to mRNA, which is used as a template to make proteins. This latter step is known as mRNA translation. In order to function properly, cells and organisms need to make proteins at the right time, place and in the correct amount. Thus it is critical that mRNA translation and the lifespan of an mRNA (i.e. use and availability) is carefully regulated, with improper control leading to a wide variety of diseases including cancer, metabolic, neurological and reproductive disorders. Regulating translation is also critical to industrial processes that require the efficient synthesis of particular proteins.The cellular monitoring of mRNA processing, levels, utilisation (translation) and destruction is collectively termed 'post-transcriptional control', since they take place after mRNA is transcribed, and is carried out by mRNA-binding proteins (RNA-BPs). Human cells can express >1000 RNA-BPs and, intriguingly, many of them carry out multiple unrelated functions in the processes of post-transcriptional control, i.e. they are multifunctional. However, the way that multifunctionality is coordinated and regulated is understood in only a handful of cases. This leaves a crucial gap in our knowledge since an understanding of RNA-BP coordination is vital to delineating post-transcriptional control processes and to understanding why they fail and how to manipulate them for therapeutic or biotechnology purposes.We recently revealed that numerous RNA-BPs are subject to two different forms of chemical modification at the same place in the proteins. These modifications, termed 'acetylation' and 'methylation', cannot occur on the same place in the protein at the same time, meaning that the RNA-BP can exist in three states: unmodified, acetylated or methylated, with the different chemical properties of each modification state having the potential to confer altered functions to a protein or changing its ability to interact with other proteins. Fascinatingly, these modifications are very well characterised for their functions on proteins called histones, which help pack and regulate the cell DNA in the nucleus, where they are known to work like switches for different histone functions. However, such switches have never previously been described for RNA-BPs, and we hypothesise that we have uncovered a new regulatory mechanism for RNA-BPs that may explain how their multifunctionality is coordinated.We aim to test this hypothesis using a well-characterised, multifunctional RNA-BP called Poly(A)-binding protein (PABP) 1, the dysregulation of which impacts physiological processes such as fertility, metabolism and learning/memory. We have identified an acetylation/methylation switch in PABP1 at a site within the protein that is critical for its interactions with many other proteins that are required for the various functions of PABP1. We will test the switch's ability to regulate the binding of specific PABP1 partner proteins and test the effects of the acetylation or methylation on the functions of PABP1 in post-transcriptional control. We will also find out which cellular enzymes regulate the PABP1 switch and under what cellular circumstances (e.g. healthy growing cells or unhealthy cells). By carrying out this study we aim to uncover the regulation of RNA-BPs, and thus post-transcriptional control, by acetylation/methylation switches and open up a new area of research akin to the now well-understood field of transcription control by similar switches in histones. In doing so, we will increase our understanding of the critical mechanisms that regulate gene expression to ensure the proper functioning and health of cells within the body.