ReviewThe critical impacts of small RNA biogenesis proteins on aging, longevity and age-related diseases
Introduction
Organisms' genomes abound with regions that are transcribed but not annotated to encode proteins. At the same time, products of such regions, particularly non-coding RNAs, realize essential regulatory functions in the majority of fundamental biological and pathological processes (Pang et al., 2018). Progress in RNA sequencing and bioinformatics approaches gives a perspective to study all transcribed sequences, which are represented by numerous classes of biomolecules having a unique role in determining longevity and aging rate. The pool of genes and proteins that control this intracellular “RNA world” has been well described for simple organisms (Kim and Lee, 2019). However, the principles of their functioning in post-transcriptional stages and their influence on longevity have not been precisely formulated, probably due to the large number of contributing units or complex relationships between regulators and products or uncountable interactions. In the present review, we focused on critical proteins that control the biogenesis of small RNAs, for processing of double-stranded RNAs (dsRNA) and for generation of small RNAs themselves.
In Drosophila melanogaster studies, it was found that aging causes a decrease in the proportion of heterochromatin, an abolition of silencing of reporter genes in regions of constitutive heterochromatin, as well as an increase in transposons’ activity (Li et al., 2013; Wood et al., 2016). In turn, transposons can have a mutagenic effect by altering coding or regulatory sequences (Lenart et al., 2018; Sturm et al., 2015). At the same time, caloric restriction leading to lifespan extension prevents an age-dependent increase in the activity of heterochromatin and transposon genes (Wood et al., 2016). Impacts that support repression of heterochromatin and silencing of transposons open up prospects for the development of preventive methods to reduce the pathogenic activity of heterochromatin genes, as well as to eliminate damage caused by uncontrolled activation of transposons, which can lead to an extension of healthspan and lifespan (Wood et al., 2016).
Small regulatory RNAs are a natural mechanism that controls transposons’ activity and fight transcriptome/genome instabilities. Small RNAs include three large classes encoding in our genome and differ by the mechanism of their biogenesis and the type of protein with which they are associated. These are endogenous short interfering RNAs (endo-siRNAs) with a length of 21 nucleotides, microRNAs (miRNAs) with a length of 22 nucleotides and P-element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) with a length of 24–32 nucleotides. Main targets of their activity are mRNAs and transposons. In addition, there are exogenous short interfering RNAs (exo-siRNAs) that are derived from viral double-stranded RNAs (dsRNAs) or artificial dsRNAs, and are aimed to restrict viral and external activity. Small RNAs are involved in controlling organism development, forming various organs and tissues, coordinating a diversity of biological processes, including metabolism, maintaining genome stability and immune response (Iatsenko et al., 2013; Kim et al., 2009; Okamura and Lai, 2008). A decrease in the activity of small RNAs occurs during aging (Kato et al., 2011; Yu et al., 2019). A recent study of gene networks that control the processing and transcription of miRNAs in Caenorhabditis elegans has shown their close interaction with transcription factors and aging-related miRNAs. At the same time, there is an inverse positive relationship that determines a directional miRNA-associated mechanism of an age-related decline in functions at the molecular level (Inukai et al., 2018).
Biogenesis and functioning of small RNAs are directly determined by proteins of the ribonuclease III (RNase III) family (including Drosha and Dicer proteins), the Argonaute family (including Argonaute and PIWI subfamilies) and a set of partner proteins (Kim et al., 2009; Okamura and Lai, 2008). Dicer-like and Argonaute proteins exhibit various transcriptional patterns and numerous para-/orthologs in different taxons of animals and plants (Gao et al., 2014; Song and Rossi, 2017; Wynant et al., 2017; Zhang et al., 2018b). However, a number of partner proteins are specific for animals. In particular, TRBP, PACT and GW182 are an exclusively animals’ trait (Zhang et al., 2018b). Dicer-like, Argonaute, RNA-dependent RNA polymerase and related small interfering RNA molecules have been identified and characterized in several fungal species (Jeseničnik et al., 2019).
Small RNA biogenesis proteins are critical for embryonic development of tissues and organs, as well as for maintaining normal functioning in adult animals (Aryal et al., 2019; Bartram et al., 2015; Bernstein et al., 2003; Harfe et al., 2005; Iwasaki et al., 2015; Khan et al., 2017; Liu et al., 2004; Sasaki et al., 2003; Wienholds et al., 2003). In this article, we focused on the role of small RNA biogenesis proteins in determining aging and longevity of animals, and on the involvement of their deregulation in age-related pathological processes and diseases.
Section snippets
Key proteins of small RNA biogenesis machinery
Drosha and Dicers are members of the RNase III protein family. These enzymes are essential for the processing of double-stranded RNAs (dsRNAs) and stem-loop RNA structures followed by the formation of functional siRNAs and miRNAs. The Drosha protein participates in the biogenesis of miRNAs (but not siRNAs). Drosha cuts their RNA substrate duplexes (pri-miRNAs) producing short hairpin RNA molecules (pre-miRNAs). Members of the Dicer family are involved in the formation of both siRNAs and miRNAs,
The involvement of small RNA biogenesis proteins in stress response
Aging is usually characterized by an impaired ability to cope with environmental and physiological stressors. Small RNA biogenesis proteins are tightly coupled with mechanisms of stress response (De Cauwer et al., 2018; Emde et al., 2015; Emde and Hornstein, 2014; Nidadavolu et al., 2013; Olejniczak et al., 2018). In particular, an aging-related decrease in the Dicer expression reduces stress tolerance, while the increased stress further suppresses Dicer accelerating aging-associated changes
Age-related changes in the expression of small RNA biogenesis proteins
Recently, it has been shown that centenarians have higher transcription of miRNAs and genes encoding special enzymes associated with small RNA biogenesis, including RNA polymerase II, Drosha, Exportin 5 and Dicer, compared to octogenarians. Authors of the study proposes that the expression of miRNAs and proteins of their biogenesis decreases during ordinary aging (octogenarians) but not in extraordinary aging (centenarians). However, this model does not account the proportion of octogenarians
Small RNA biogenesis proteins as determinants of lifespan in model animals
As previously described, proteins involved in small RNA biogenesis have higher expression in individuals with exceptional longevity (Borrás et al., 2017). A number of studies carried on model organisms with changed activity of genes encoding these proteins have demonstrated their critical role in determining health, lifespan and aging rate. Additionally, small RNA biogenesis proteins are associated with the efficiency of some life-extending manipulations such as dietary restriction.
Constitutive
The role of small RNA biogenesis proteins in cancer
Deregulation of small RNA biogenesis proteins, particularly Drosha, Dicer, Ago2, Piwil2, plays an essential role in the development and progression of different types of cancer (Hata and Kashima, 2016; Vo et al., 2016; Han et al., 2017; Joyce et al., 2018; Ye et al., 2015).
The role of Dicer in oncological diseases is most studied among other small RNA biogenesis proteins. Dicer mutations can lead to specific syndromes in humans, such as Dicer1 syndrome or GLOW (Global developmental delay, Lung
The role of small RNA biogenesis proteins in pathogenesis of other age-related diseases
It is known that altered expression of proteins involved in small RNA biogenesis is one of the key traits of other age-related diseases, including inflammatory, neurological, cardiovascular, metabolic, immune disorders (Baulina et al., 2016; Chmielarz et al., 2017; Gascon and Gao, 2012; Olejniczak et al., 2018; Reis et al., 2016; Wang et al., 2018; Yan et al., 2013).
Dicer regulates the activity of the NLRP3 inflammasome, a heterotrimer consisting of the NLR protein, the ASC protein and the
Conclusion
In the present work, we have essayed actual data on the role of small RNA biogenesis proteins in the lifespan regulation, aging process and pathogenesis of age-related human diseases. During aging, depending on the tissue and physiological state of an individual, both a critical decrease in the expression of small RNA biogenesis proteins and their excessive activation can take place. On the one hand, a deactivation of these proteins interlocks with changes in miRNA, siRNA and piRNA levels that
Funding
EP, IS, LK carried out the work within the Grant of the President of the Russian Federation № MK-1229.2019.4 “The role of genes of small RNA biogenesis and regulation in the lifespan control and aging of Drosophila melanogaster”. AM carried out the work within the framework of the state task on the theme “Molecular-genetic mechanisms of aging, lifespan, and stress resistance of Drosophila melanogaster”, state registration № АААА-А18-118011120004-5.
Declaration of Competing Interest
The authors declare that they have no conflicts of interest.
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