Review
Non-coding RNAs: Emerging from the discovery to therapeutic applications

https://doi.org/10.1016/j.bcp.2021.114469Get rights and content

Abstract

The knowledge about non-coding RNAs (ncRNAs) is rapidly increasing with new data continuously emerging, regarding their diverse types, applications, and roles. Particular attention has been given to ncRNA with regulatory functions, which may have a critical role both in biological and pathological conditions. As a result of the diversity of ncRNAs and their ubiquitous involvement in several biologic processes, ncRNA started to be considered in the biomedical field, with immense potential to be exploited either as biomarkers or as therapeutic agents in certain pathologies. Indeed, ncRNA-based therapeutics have been proposed in many disorders and some even reached clinical trials. However, to prepare an RNA product suitable for pharmacological applications, certain criteria must be fulfilled, and it has to be guaranteed RNA purity, stability, and bioactivity. So, in this review, the different types of ncRNAs are identified and characterized, by describing their biogenesis, functions, and applications. A perspective on the main challenges and innovative approaches for the future and broad therapeutic application of RNA is also presented.

Section snippets

Non-coding RNA

Gene expression is an essential process for all living organisms and its regulation defines the development and homeostasis of cells and tissues [1]. Francis Crick's “central dogma” stated that genetic information derived from DNA, is transcribed in its intermediary - the messenger RNA (mRNA) – to finally be translated into proteins [2], [3]. In this context, for several years, proteins were considered as the functional product of genetic information, although the genes encoding proteins

Housekeeping non-coding RNAs

Several classes of ncRNAs are required for the translation of mRNA into proteins and can also be involved in the regulation of this mechanism [1]. Thus, housekeeping ncRNAs are expressed constitutively and ubiquitously, and they are essential for cell viability and routine cell maintenance, being present in all cell types. The tRNAs are as important as the mRNA for protein translation, since they have the function of decoding the mRNA sequence to synthesize a peptide or protein, specifically

Regulatory non-coding RNA

In the 1990 s, the discovery of regulatory ncRNAs was a key step in the understanding of ncRNAs. In 1993, Lee and colleagues identified the first RNA interference (RNAi) in the nematode Caenorhabditis elegans, characterizing it as a non-protein-coding transcript named lineage-4 (lin-4). Lin-4 was shown to negatively regulate lineage protein 14 (lin-14) by imperfect complementary binding to its 3′ UTR mRNA [117], [118]. These ncRNAs play an important role in many biological processes through the

ncRNA Applications: Challenges and perspectives

For the preparation of an RNA product suitable for pharmacological applications, certain characteristics have to be considered like the quantity required, the product quality, stability, safety, and biological activity until reaching the target location (nucleus, cytoplasm or specific organelles). So, to advance with the application of RNA as biopharmaceuticals it is imperative to overcome the problems associated with the production, purification, stability and delivery of RNA.

Due to the

CRediT authorship contribution statement

B. Baptista: Conceptualization, Investigation, Writing - original draft, Writing - review & editing. M. Riscado: Conceptualization, Investigation, Writing - original draft, Writing - review & editing. J.A. Queiroz: Conceptualization, Validation, Writing - review & editing. C. Pichon: Conceptualization, Validation, Writing - review & editing, Supervision. F. Sousa: Conceptualization, Validation, Writing - review & editing, Supervision, Project administration, Funding acquisition.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by the Portuguese Foundation for Science and Technology (FCT), through the project UIDB/00709/2020, and by the project PTDC/BII-BBF/29496/2017 (PUREmiRSILs) funded by FEDER, through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI), and by national funds (OE), through FCT/MCTES. Baptista B. also acknowledges a fellowship within the project PUREmiRSILs.

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