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

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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.