What Is The Job Of Rna Polymerase – Transcription in eukaryotic cells is carried out by three RNA polymerases. RNA polymerase I synthesizes most rRNAs, while RNA polymerase II transcribes all mRNAs and many non-coding RNAs. The largest of the three polymerases is RNA polymerase III (Pol III) which transcribes a variety of short non-coding RNAs including tRNAs and 5S rRNA, in addition to other small RNAs such as snRNAs, snoRNAs, SINEs, 7SL RNA, Y RNA. , and the U6 spilceosomal RNA. Pol III-mediated transcription is highly dynamic and regulated in response to changes in cell growth, cell proliferation, and stress. Pol III-generated transcripts are involved in a wide variety of cellular processes, including translation, genome and transcriptome regulation, and RNA processing, with Pol III dys-regulation implicated in diseases such as and leukodystrophy, Alzheimer’s, fragile X syndrome and various cancers. More recently, Pol III was identified as an evolutionarily conserved determinant of organismal life that acts downstream of mTORC1. Pol III inhibition extends lifespan in yeast, worms and flies, and in worms and flies it acts from the gut and intestinal stem cells respectively to achieve this. Interestingly, Pol III activation achieved through the impairment of its master repressor, Maf1, has also been shown to promote longevity in model organisms, including mice. In this review, we introduce the Pol III transcription apparatus and review the current understanding of the role of RNA Pol III in aging and life in various model organisms. We then discuss the potential of Pol III as a therapeutic target to improve aging health in humans.

Transcription of the eukaryotic nuclear genome is carried out by three evolutionarily conserved multi-subunit RNA polymerases (Pols), each of which transcribes a distinct set of genes. A large part of the nuclear genome is transcribed by Pol II to generate coding and non-coding RNAs. In contrast, Pol I only transcribes a single gene, although present in multiple copies in the genome, to produce the precursor to most rRNAs. While Pol I and III transcribe fewer genes, they generate some of the most abundant cellular RNAs that account for much of cellular transcriptional activity ( White, 2008 ; Vannini and Cramer, 2012 ; Arimbasseri and Maraia, 2016 ).

What Is The Job Of Rna Polymerase

With 17 subunits, Pol III is the largest of the three RNA polymerases (Vannini and Cramer, 2012). It transcribes many abundant, non-coding RNAs (up to a few hundred bases in length), some of which are involved in translation, such as 5S RNA and tRNA, some of which are involved in RNA processing, such as an amount of sn or tRNA. snoRNAs, while others play regulatory roles, such as 7SK RNA. Indeed, the list of genes transcribed by Pol III has been expanding in recent times (Acker et al., 2013; Turowski and Tollervey, 2016). Pol III function has also extended beyond the canonical role in nuclear genome transcription to now include responses to DNA viruses and recombination-mediated homologous repair of DNA double-strand breaks (Chiu et al ., 2009; Liu et al., 2021). Pol III-mediated transcription is involved in a wide range of biological processes, including cell growth and organism (Grewal et al., 2005, 2007; Halaschek-Wiener et al., 2005; Chiu et al., 2009 ; Marshall et al., 2012). ; Rideout et al., 2012), cell cycle (White et al., 1995), stemness and differentiation (Wong et al., 2011; Alla and Cairns, 2014; Van Bortle et al., 2017; Chen et al., 2018 ), development (Schmitt et al., 2014), regeneration (Yeganeh et al., 2019), and cellular responses to stress (Upadhya et al., 2002; Gouge et al., 2015). As a result, Pol III subunits have been implicated in a wide variety of disease states, reviewed by (Yeganeh and Hernandez, 2020).

T7 Rna Polymerase

The recruitment of Pol III to its target genes is facilitated by a number of dedicated basal transcription factors (TFs), where the exact combination of TFs involved is dictated by the particular promoter present (reviewed in Schramm and Hernandez (2002). promoter (Type I-III) recruits Pol III, with all three requiring the binding of TFIIIB, a 3-subunit TF containing the TATA box-binding protein (TBP). Type I and II promoters are internal genes, while type III. resides in the 5′ flanking region. Type II is present in tRNA genes and additionally requires TFIIIC, a 6-subunit TF that binds intragenic promoter elements. The type I promoter is responsible for the transcription of 5S rRNA genes and employs an additional factor, TFIIIA, for Type III is distinguished from Type I and II promoters because they do not require TFIIIC for Pol III-mediated transcription, but employ SNAPc, a TF also associated with Pol II transcription (Schramm and Hernandez, 2002). types and TFs are essentially conserved in wide evolutionary distance, but with some specific differences of phyla (Schramm and Hernandez, 2002; Teichmann et al., 2010). Additional TFs that regulate Pol III activity include Myc, a transcriptional activator that can act on all three Pols (Gomez-Roman et al., 2003; Campbell and White, 2014), as well as the Maf1 protein, a repressor highly conserved of Pol III. activity (Upadhya et al., 2002; Vorländer et al., 2020). Because of the critical functions of RNA Pol III in growth and differentiation, it is perhaps not surprising that signaling pathways that influence these cellular processes can also interact with and regulate Pol III activity (Willis and Moir, 2018). Probably the most studied of these is the highly conserved mTOR pathway (Wei et al., 2009; Liu and Sabatini, 2020), which we will discuss in the following section.

The increased proportion of the elderly in our societies has stimulated the study of the biology of aging with the hope that a thorough understanding of the mechanisms of aging will bring us closer to identifying targets for intervention to help prevent or to improve the diseases of aging (Partridge et al. , 2018). Indeed, several decades of research have shown that aging itself is highly plastic and can be modulated through genetic, dietary and pharmacological means. For example, reducing the activity of the Target of Rapamycin kinase Complex 1 (TORC1) can promote longevity and health in a number of animal species (Erdogan et al., 2016; Liu and Sabatini, 2020). The central component of the complex is mTOR, a Ser/Thr kinase of 289 kDa that belongs to the PI3K-related protein kinase (PIKK) family (Liu and Sabatini, 2020). TORC1 is activated in the presence of nutrients and growth factors, essentially acting to promote anabolic pathways while suppressing catabolism. Given that protein synthesis is one of the most energy-intensive anabolic processes required for growth (Buttgereit and Brand, 1995), TORC1 tightly regulates the supply of protein synthetic machinery, including the regulation of Pol III activity. . Indeed, TORC1 has also been shown to localize to the promoters of a number of rRNA and tRNA genes and control their transcription (Li et al., 2006). It is this link between TORC1 and Pol III that initially prompted us to investigate the role of Pol III in the aging of the organism.

It is possible to reduce the activity of RNA Polymerase III in model organisms by reducing individual subunits of this complex, through a partial or restricted loss of function, thus avoiding the lethality of the organism that follows the complete loss . We found that in the nematode worm Caenorhabditis elegans, RNAi targeting the rpc-1 gene, which encodes the largest of the 17 Pol III subunits (ortholog of yeast RPC160), significantly extended the lifespan of the organism (Filer et al. , 2017). This was also true in the fruit fly Drosophila melanogaster, where RNAi of dC160 (the fly orthologue of RPC160) extended lifespan, as did a heterozygous mutant of another Pol III subunit dC53 ( Filer et et al., 2017). Indeed, inducible loss of RPC160 in yeast also extended chronological life, thus demonstrating broad evolutionary conservation ( Filer et al., 2017 ).

Since the longevity of an organism can be determined by a specific organ, we tested if this was also the case for Pol III (Filer et al., 2017). Since the gut has previously been shown to be important for longevity modulation in worms and flies, we focused our attention on this tissue ( Libina et al., 2003 ; Piper et al., 2008 ). We showed that inhibition of Pol III activity in the adult worm or fly intestine with tissue-specific RNAi was sufficient to extend lifespan; and more specifically in flies, longevity was also achieved by inhibiting Pol III exclusively in intestinal stem cells (ISCs) ( Filer et al., 2017 ). In contrast, downregulation of Pol III in neurons and the fat body of flies had little or no effect on lifespan (Filer et al., 2017).

What Is The Difference Between Transcription And Translation?

With advanced age, the function of many organ systems and tissues deteriorates, contributing to physiological decline, multimorbidity and finally death (Rera et al., 2012; Ezcurra et al., 2018; Funk et al. , 2020). For example, in worms and flies, the intestinal luminal wall begins to break down and become more porous with advancing age, with similar changes in intestinal permeability and barrier function reported in mammals, including humans (Funk et et al., 2020). We found that Pol III knockdown-induced longevity was associated with amelioration of age-related intestinal pathology and its functional decline ( Filer et al., 2017 ). Critically this suggests that Pol III reduction is both a target for longevity and age-related health, and together with the intestinal longevity data points to intestinal longevity.

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