The forerunners and successful partnerships behind the BioNTech mRNA vaccine.

The discovery of nucleic acids stands as a paramount achievement in the history of scientific endeavors. By applying transformative advancements in the fields of chemistry and physics to biological systems, researchers unveiled the enigmatic nature of life. Notably, messenger RNA (mRNA) emerged as a crucial player in this profound revelation, serving as a transient intermediary for genetic information transfer between genes and proteins. Groundbreaking investigations carried out from 1944 to 1961 led to the initial identification of this pivotal molecule, captivating scientific interest for the past three decades. The field of mRNA research has witnessed a transformative shift owing to the development of cap analogs and nucleotide modifications. This revolutionary progress has fostered a new generation of potent therapeutics. Prior to the advent of the coronavirus pandemic, numerous scientists had already begun exploring the unique properties of mRNA. However, with the onset of the pandemic, mRNA catapulted into the limelight as a heroic agent, providing the foundation for highly effective vaccines that have played a crucial role in mitigating the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The successive generations of cap analogs have significantly enhanced the translation efficacy of mRNA, while the discovery of suitable purification, packaging, and delivery methods has paved the way for groundbreaking medical breakthroughs. Pioneers in the field such as Katalin Karikó, Drew Weissman, Edward Darzynkiewicz, Robert Rhodes, Ugur Sahin, and Ozlem Tureci have made significant contributions during the early stages of mRNA research, warranting acknowledgement for their visionary endeavors. The narrative of mRNA represents a remarkable journey marked by a succession of breakthroughs in a discipline that holds immense promise for the future of medicine. Thanks to the pioneering work of these exceptional scientists, we are well-positioned to unlock the full potential of this extraordinary molecule, ushering in a new era of medical advancements.

A germline-targeted genetic screen for xrn-2 suppressors identifies a novel gene C34C12.2 in Caenorhabditis elegans.

XRN2 is an evolutionarily conserved 5'-to-3' exoribonuclease, which degrades or trims various types of RNA in the nucleus. Although XRN-2 is essential for embryogenesis, larval development and reproduction in Caenorhabditis elegans, relevant molecular pathways remain unidentified. Here we create a germline-specific xrn-2 conditional mutant and perform a mutagenesis screen for suppressors of sterility. Loss-of-function alleles of dpy-10, osr-1, ptr-6 and C34C12.2 genes are identified. Depletion of DPY-10, OSR-1 or PTR-6 increases expression of gpdh-1 that encodes a glycerol-3-phosphate dehydrogenase, thereby elevates glycerol accumulation to suppress sterility of the mutant. The C34C12.2 protein is predominantly localized in the nucleolus of germ cells and shows a similarity to Saccharomyces cerevisiae Net1, which is involved in rDNA silencing. Depletion of NRDE-2, a putative interacting partner of C34C12.2 and a component of the nuclear RNAi machinery, restores fertility to the xrn-2 conditional mutant. These results may help to identify an essential role of XRN-2 in germline development.

Nuclear RNA Regulation by XRN2 and XTBD Family Proteins.

XRN2 is a 5'-to-3' exoribonuclease that is predominantly localized in the nucleus. By degrading or trimming various classes of RNA, XRN2 contributes to essential processes in gene expression such as transcription termination and ribosome biogenesis. Despite limited substrate specificity in vitro, XRN2 targets a specific subset of RNA by interacting with other proteins in cells. Here we review the functions of proteins that have an evolutionarily conserved XRN2-binding domain, XTBD. These proteins modulate activity of XRN2 by stabilizing it, controlling its subcellular localization or recruiting it to specific RNA targets, and thereby impact on various cellular processes.Key words: RNA regulation, XRN2, XTBD, ribosome biogenesis, subcellular localization.

The Transcription Factor Elf3 Is Essential for a Successful Mesenchymal to Epithelial Transition.

The epithelial to mesenchymal transition (EMT) and the mesenchymal to epithelial transition (MET) are two critical biological processes that are involved in both physiological events such as embryogenesis and development and also pathological events such as tumorigenesis. They present with dramatic changes in cellular morphology and gene expression exhibiting acute changes in E-cadherin expression. Despite the comprehensive understanding of EMT, the regulation of MET is far from being understood. To find novel regulators of MET, we hypothesized that such factors would correlate with Cdh1 expression. Bioinformatics examination of several expression profiles suggested Elf3 as a strong candidate. Depletion of Elf3 at the onset of MET severely impaired the progression to the epithelial state. This MET defect was explained, in part, by the absence of E-cadherin at the plasma membrane. Moreover, during MET, ELF3 interacts with the Grhl3 promoter and activates its expression. Our findings present novel insights into the regulation of MET and reveal ELF3 as an indispensable guardian of the epithelial state. A better understanding of MET will, eventually, lead to better management of metastatic cancers.