Foreword

Discoveries over the past decade enabled a paradigm shift in RNA biology. RNA-binding proteins (RBPs) are critical effectors of gene expression by regulating all aspects of RNA life, including transcription, splicing, intracellular trafficking, translation, and decay. Therefore, their malfunction underlies the pathogenesis of many diseases, including cancers and neurodegenerative disorders. Conversely, increasing evidence suggests the emerging role of RNA in the regulation of genome organization and gene expression, as well as the activity or location of RBPs besides its established role as a messenger between DNA and protein. Together with an accumulating understanding of the regulatory mechanisms of RBPs, insights obtained from a system-wide analysis of regulatory RNA are facilitating the development of a new therapeutic intervention to treat malignancies.

In this Current Topics section, I organized four papers consisting of one review paper and three regular articles. The first review article entitled “Between Order and Chaos: Understanding the Mechanism and Pathology of RAN Translation,” written by Dr. Asano and Dr. Reyes, provides an overview of the repeat-associated non-AUG (RAN) translation and its implication in the pathophysiology of repeat expansion diseases. RAN translation is a pathogenic mechanism in which repetitive sequences are translated into aggregation-prone proteins from multiple reading frames, even without a canonical AUG start codon. RAN translation has now attracted strong attention as a therapeutic target as it occurs in the context of a dozen of disease-linked repeat expansions. Dr. Asano and Dr. Reyes will discuss recent advances in understanding the regulatory mechanisms controlling RAN translation and its implication in diseases with a special focus on Fragile X Tremor/Ataxia Syndrome.

The second regular article entitled “BAY61-3606 Alters snRNP Composition and Enhances Usage of Suboptimal Splice Acceptor Site” written by Tomita et al. has reported their discovery of a small compound, BAY-3606, which changed the cellular snRNP composition with the activity of enhancing splicing at the mutated 3′ splice site of the reporter gene. Given that the splice site selection is one of the key steps for correct splicing reaction, and that mutations in the acceptor or donor areas of splice sites can become detrimental to a human individual, leading to diseases including cancer, dementia, and epilepsy, BAY61-3606 may be useful for analyses of splicing mechanisms, which may contribute to therapeutics to human diseases. The third regular article entitled “Neuronal RNA-Binding Protein HuD Interacts with Translation Initiation Factor eIF3” from the Fujiwara group has provided important information on the initiation of translation, which plays a major role in the regulation of protein synthesis. They demonstrated that neuronal RBP HuD interacts with eIF3 via eIF3b in an RNA-independent manner. They also report a beautiful set of co-immunoprecipitation experiments showing that a linker region of HuD is responsible for its binding to eIF3. Importantly, the regions of other Hu proteins homologous to this region of HuD are shown to be the eIF3-binding site. Since malfunctions of HuD are involved in various neuronal diseases, such as neuroblastoma, this study will provide a valuable clue to the understanding of how the cooperative interaction of HuD and eIF3 leads to translation stimulation. The fourth regular article entitled “Fission Yeast PUF Proteins Puf3 and Puf4 Are Novel Regulators of PI4P5K Signaling” from the Sugiura group has provided a new concept of the regulatory mechanism of PI4,5P2 signaling by RNA-binding proteins. The authors’ genetic screening using the fission yeast model system has identified the PUF family RNA-binding protein Puf3 and Puf4 as a regulator of PI4P5K by demonstrating that Puf3 and Puf4 regulate mRNA levels of PI4P5K, which requires RNA-binding activity of Puf3/Puf4. These data suggest the existence of a novel precise mechanism to regulate PI4P5K expression levels by RNA-binding protein PUFs.

I believe that these review and regular articles provide emerging aspects in the field of RNA biology with an emphasis on molecular mechanisms of disease and therapeutic interventions.