RNAs are extremely important molecules inside the cell, which perform many different functions. For example, messenger RNAs, transfer RNAs and ribosomal RNAs are involved in protein synthesis, whereas noncoding RNAs have numerous regulatory roles. Ribonucleases (RNases) are the enzymes responsible for the processing and degradation of all types of RNAs, having multiple roles in every aspect of RNA metabolism. However, the involvement of RNases in disease is still not well understood. This review focuses on the involvement of the RNase II/RNB family of 3′–5′ exoribonucleases in human disease. This can be attributed to direct effects, whereby mutations in the eukaryotic enzymes of this family [defective in sister chromatid joining (Dis3; or Rrp44), Dis3‐like exonuclease 1 (Dis3L1; or Dis3L) and Dis3‐like exonuclease 2 (Dis3L2)] are associated with a disease, or indirect effects, whereby mutations in the prokaryotic counterparts of RNase II/RNB family (RNase II and/or RNase R) affect the physiology and virulence of several human pathogens. In this review, we compare the structural and biochemical characteristics of the members of the RNase II/RNB family of enzymes. The outcomes of mutations impacting enzymatic function are revisited, in terms of both the direct and indirect effects on disease. Furthermore, we also describe the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) viral exoribonuclease and its importance to combat the COVID‐19 pandemic. As a result, RNases may be a good therapeutic target to reduce bacterial and viral pathogenicity. These are the two perspectives on RNase II/RNB family enzymes that are presented in this review.
A long scientific journey has led to prominent technological advances in the RNA field, and several new types of molecules have been discovered, from non-coding RNAs (ncRNAs) to riboswitches, small interfering RNAs (siRNAs) and CRISPR systems. Such findings, together with the recognition of the advantages of RNA in terms of its functional performance, have attracted the attention of synthetic biologists to create potent RNA-based tools for biotechnological and medical applications. In this review, we have gathered the knowledge on the connection between RNA metabolism and pathogenesis in Gram-positive and Gram-negative bacteria. We further discuss how RNA techniques have contributed to the building of this knowledge and the development of new tools in synthetic biology for the diagnosis and treatment of diseases caused by pathogenic microorganisms. Infectious diseases are still a world-leading cause of death and morbidity, and RNA-based therapeutics have arisen as an alternative way to achieve success. There are still obstacles to overcome in its application, but much progress has been made in a fast and effective manner, paving the way for the solid establishment of RNA-based therapies in the future.
Exoribonucleases from the RNB-family of enzymes are widely distributed in nature. DIS3 is the eukaryotic homolog of the bacterial exoribonuclease II and is the only catalytic subunit of the core exosome complex. In humans, there are three members of DIS3 family that can be distinguished according to the sequence conservation of the active site: DIS3, DIS3L (DIS3L1) and DIS3L2. Unlike its family counterparts, DIS3L2 does not interact with the exosome since it lacks the PIN domain, which is essential for the interaction with this multiprotein complex. Dis3L2 is involved in several cellular mechanisms, such as apoptosis, cellular differentiation and proliferation and its mutations have been associated with Wilms tumor formation and Perlman syndrome in children. Distinct studies on Dis3L2 enzyme unraveled a novel eukaryotic RNA decay pathway that challenged the models already established. Dis3L2 activity is stimulated by the addition of untemplated uridine residues to mRNAs, tRNAs, microRNAs, snRNAs among other classes of RNA. The first insight on the uridylation involvement in controlling the stability of poly(A)-containing mRNAs was reported in S. pombe. However, the precise mechanism of action of this enzyme is not yet fully understood. In this work, the activity of fission yeast Dis3L2 mutant proteins was analyzed over different RNA substrates. The aim was to characterize the amino acid residues that distinguish Dis3L2 substrate specificities regarding its family homologues, namely the preference for uracil residues. The results show that some of the mutant Dis3L2 ribonucleases lose or acquire activity regarding the degradation of different RNAs. Furthermore, this will enable us to understand the mechanism of action of Dis3L2 and its function in different eukaryotic cells.
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