RNA Polymerase III, Ageing and Longevity

Abstract

Transcription in eukaryotic cells is performed by three RNA polymerases. RNA polymerase I synthesises most rRNAs, whilst 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 the 5S rRNA, in addition to other small RNAs such as snRNAs, snoRNAs, SINEs, 7SL RNA, Y RNA, and 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 including leukodystrophy, Alzheimer’s, Fragile X-syndrome and various cancers. More recently, Pol III was identified as an evolutionarily conserved determinant of organismal lifespan acting downstream of mTORC1. Pol III inhibition extends lifespan in yeast, worms and flies, and in worms and flies acts from the intestine and intestinal stem cells respectively to achieve this. Intriguingly, Pol III activation achieved through 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 RNA Pol III’s role in ageing and lifespan in different model organisms. We then discuss the potential of Pol III as a therapeutic target to improve age-related health in humans.

Epigenetic alterations in gut and brain of adult rats after oral administration of miR-320-3p and miR-375-3p at mid-lactation, and preventive potential of miR-320-3p on early weaning stress

“…The RNA polymerase III is now considered linked to aging and longevity through its action on TORC and insulin genes as well as its activity on genes related to telomerase activity. 51, 52 However, we have shown only an immediate effect on the chromatin complexes related to H3K4me3, as well as an absence of long-term effect on polr3d mRNA. The miR-320-3p has been studied for post-transcriptional gene silencing in the cytoplasm of rat endothelial and cardiac cell cultures derived from diabetes situations, on several genes among which the heat shock protein family B (small) member 6 .…”

Timing of TORC1 inhibition dictates Pol III involvement in longevity inCaenorhabditis elegans

“…Both TOR signalling and RNA Polymerase III are important regulators of anabolic processes, and control an wide array of cellular functions including reproduction and lifespan 16 . Here we show that TOR and Pol III interact in a time dependent manner, and that knockdown of each component individually, sequentially or in parallel influences the outcome of both reproductive and longevity processes (Fig.…”

“…Other Pol III transcripts include small nuclear (snRNAs) and small nucleolar (snoRNAs) both of which are implicated in RNA processing, the 7SK snRNAs that plays role in regulating transcription, as well as other small RNAs including Y RNA, L RNA, vault RNA and U6 spliceosomal RNA 3,4 Pol III-mediated transcription regulates a wide range of biological processes including cell and organismal growth [5][6][7][8] , the cell cycle 9 , differentiation 8,10,11 , development 12 , regeneration 13 and cellular responses to stress 14 . Pol III subunits have also been implicated in a wide variety of disease states and lifespan [15][16][17] .…”

STAT3 promotes RNA polymerase III-directed transcription by controlling the miR-106a-5p/TP73 axis

“…In addition to Pol III general transcription factors, oncogenic factor (c-MYC), tumour suppressor (p53) and signalling transduction factors (JNK and PTEN/AKT) can also tightly modulate Pol III – mediated transcription ( Gomez-Roman et al, 2003; Crighton et al, 2003; Sriskanthadevan-Pirahas et al, 2018; Zhong and Johnson, 2009; Woiwode et al, 2008 ). MAF1, a well-characterized factor repressing Pol III-directed transcription ( Kulaberoglu et al, 2021; Bonhoure et al, 2020 ), has recently been shown to regulate osteoblast differentiation and bone mass formation ( Phillips et al, 2022 ); and this factor has also been confirmed to improve cardiac hypertrophy and inhibit the synthesis of Pol III products by interacting with ERK ( Sun et al, 2019 ). It has been reported that tRNA (tRNA) biogenesis and specific tRNAs such as tRNA Leu -CAA and tRNA Tyr -GTA are required for the regulation of senescence ( Guillon et al, 2011 ).…”