Guardian of Genetic Messenger-RNA-Binding Proteins

Abstract

RNA in cells is always associated with RNA-binding proteins that regulate all aspects of RNA metabolism including RNA splicing, export from the nucleus, RNA localization, mRNA turn-over as well as translation. Given their diverse functions, cells express a variety of RNA-binding proteins, which play important roles in the pathologies of a number of diseases. In this review we focus on the effect of alcohol on different RNA-binding proteins and their possible contribution to alcohol-related disorders, and discuss the role of these proteins in the development of neurological diseases and cancer. We further discuss the conventional methods and newer techniques that are employed to identify RNA-binding proteins.

Keywords: RNA-binding proteins; alcohol; cancer; gene expression; mRNA splicing; mRNA stability; neurological diseases.

Figure 1

RNA-binding proteins and their role in RNA metabolism: Genomic DNA is transcribed in the nucleus resulting in generation of hnRNA. RNA-binding proteins (RBP) are involved in (1) splicing and alternative splicing of hnRNA, resulting in the formation of mRNAs. Messenger RNAs are then transported from nucleus into the cytoplasm (2). In the cytoplasm, RBPs aid in the localization of mRNAs to their final destination site (3). Once in the cytoplasm, each mRNA has a specific turn-over rate (4) that can be modulated by association with selective RBPs. The turn-over rate of mRNAs in cells can be altered in response to intrinsic and extrinsic stimuli. Messenger RNAs serve as a template for translation and RBPs play an important role in translation (5).

Figure 2

A proposed mechanism of NR1 mRNA regulation in normal and chronic ethanol exposed fetal cortical neurons: The NR1 mRNA is localized in the rough endoplasmic reticulum (RER) irrespective of ethanol treatment [36]. The normal half-life of NR1 mRNA is ~15 h in cultured fetal cortical neurons (FCNs). Following chronic ethanol exposure, the half-life of NR1 mRNA increases to more than 24 h in FCNs [35]. One of the potential mechanisms that can explain increase in NR1 mRNA half-life is increased binding of GIIβ to NR1 mRNA as demonstrated previously by us [38,39]. Decline in ethanol concentration, e.g., ethanol withdrawal in chronic ethanol exposed FCNs, triggers post-translational modification, e.g., phosphorylation of GIIβ—a process that occurs in normal FCNs as well. Phosphorylation of GIIβ alters the protein conformation such that GIIβ is no longer bound to NR1 mRNA. Loss of interaction with GIIβ allows NR1 mRNA to become temporarily “naked”. Endoribonclease(s) present in the vicinity are now able to attack the NR1 mRNA, eventually leading to NR1 mRNA degradation.