Autogenous Control of 5′TOP mRNA Stability by 40S Ribosomes

Gentilella, Antonio; Morón-Duran, Francisco D.; Fuentes, Pedro Juan Barrios; Rocha, Guilherme Z.; Riaño-Canalias, Ferran; Pelletier, Joffrey; Ruiz, Marta Mesalles; Turón, Gemma; Castaño, Julio; Tauler, Albert; Bueno, Clara; Menéndez, Pablo; Kozma, Sara C.; Thomas, George

doi:10.1016/j.molcel.2017.06.005

Cited by 93 publications

(120 citation statements)

References 46 publications

(87 reference statements)

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“…PTBP1 is known as a binding factor for TOP mRNA, which contains 5' terminal oligopyrimidine tract (5'TOP) mostly found in mRNAs encoding ribosomal protein and elongation factors (Avni et al, 1997;Meyuhas, 2000), to regulate translation of the target TOP mRNA (Gismondi et al, 2014) as a cis-acting regulator . LARP1, which is known as 5'TOP mRNA binding proteins, stabilize the target 5'TOP mRNAs by forming complex with 40S ribosome subunit (Gentilella et al, 2017), In this study, SINEUP-GFP showed direct interaction with 40S, implying that SINEUP RNA with multimerization including PTBP1, 40S and the target mRNA may contribute the target mRNA stabilization. There are several reports that PTBP is recruited to cap-independent translation to stimulate translational initiation with re-modelling the target transcripts followed by supplying the small subunit (40S) to binding sites (Caceres et al, 2016;Stoneley & Willis, 2004).…”

Section: Discussionmentioning

confidence: 57%

SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies

Toki

Takahashi

Zucchelli

et al. 2019

Preprint

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SINEUPs are long non-coding RNAs (lncRNAs) that contain a SINE element, which up-regulate the translation of target mRNA and have been studied in a wide range of applications for biological and therapeutic tools, although the molecular mechanism is unclear. Here, we focused on the kinetic distribution of target mRNAs and SINEUP RNAs by performing co-transfection of expression vectors for these transcripts into human embryonic normal kidney cells (HEK293T/17) to investigate the network of translational regulation. The results showed that co-localization of target mRNAs and SINEUP RNAs in the cytoplasm was one of the key phenomena. We identified PTBP1 and HNRNPK as essential RNA binding proteins. These proteins contributed to SINEUP RNA sub-cellular distribution and to assembly of translational initiation complexes, leading to enhanced target mRNA translation. These findings will promote a better understanding of the mechanisms on the fate of regulatory RNAs implicated in efficient protein translation.

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Section: Discussionmentioning

confidence: 57%

SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies

Toki

Takahashi

Zucchelli

et al. 2019

Preprint

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“…There are tendencies that Torin1 treatment resulted in slight upregulation of TOP mRNAs, and in contrast, downregulation of nonTOP mRNAs ( Supplementary Fig.5b). Besides, TOP mRNA levels were decreased by LARP1 KD, likely indicating RNA destabilization as has been suggested ( Supplementary Fig.5b) [3][4][5] . LARP1 KD did not affect nonTOP RNA abundance.…”

supporting

confidence: 57%

LARP1 facilitates translational recovery after amino acid refeeding by preserving long poly(A)-tailed TOP mRNAs

Ogami

Oishi

Sakamoto

et al. 2019

Preprint

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Occasionally, cells must adapt to an inimical growth conditions like amino acid starvation (AAS) by downregulating protein synthesis. A class of transcripts containing 5'terminal oligopyrimidine (5'TOP) motif encodes translation-related proteins such as ribosomal proteins (RPs) and elongation factors, and therefore, their translation is severely repressed during AAS to conserve energy 1 . The RNA-binding protein LARP1 transduces amino acid signaling to TOP gene expression by controlling translation and stability of TOP mRNAs 2-6 .When released from AAS, translation machineries in turn have to be restored, however, the underlying mechanism of such re-adaptation is largely unknown. Here we show that LARP1 preserves TOP mRNAs in a long polyadenylated state during long-term AAS. We found that TOP mRNAs become highly polyadenylated when cells are in AAS or treated with the mTOR (mechanistic target of rapamycin) inhibitor Torin1. Importantly, depletion of LARP1 completely abrogated the polyadenylation of TOP mRNAs. Comprehensive analysis of poly(A) tail length using the Nanopore direct RNA sequencing revealed that TOP mRNAs are selectively polyadenylated under mTOR inhibition. Since a long poly(A) tail confers increased stability and polysome formation of TOP mRNAs, we predict that LARP1-dependent preservation of TOP mRNAs enables rapid translational resumption after the release from AAS. Results and DiscussionWe first investigated the effect of long-term AAS (~12 h) on three RP mRNAs (RPS6, RPL11 and RPL26 mRNA). Northern blotting revealed that mRNA species with slower migration rate started to accumulate constantly during AAS, while the fast migrating species that are

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“…In multicellular organisms, since it is the only known sequence element conserved among all RP genes, the 5'TOP motif is considered a key regulatory element for the coordinated control of RP synthesis. Previous studies suggest that the TOP motif provides control of both the transcription of TOP-genes (Parry et al, 2010;Shibui-Nihei et al, 2003) and the translation of TOP-mRNAs (Fonseca et al, 2018;Gentilella et al, 2017;Hamilton et al, 2006;Lahr et al, 2017;Meyuhas and Kahan, 2015;Patursky-Polischuk et al, 2014). A linear correlation of the activity of the luciferase reporters containing the Rpl28 promoter and the abundance of their transcripts (Fig.…”

Section: Discussionmentioning

confidence: 99%

Control of ribosomal protein synthesis by Microprocessor complex

Jiang

Prabhakar

Voorn

et al. 2020

Preprint

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Ribosome biogenesis in eukaryotes requires stoichiometric production and assembly of 80 ribosomal proteins (RPs) and 4 ribosomal RNAs, and its rate must be coordinated with cellular growth. The indispensable regulator of RP biosynthesis is the 5'-terminal oligopyrimidine (TOP) motif, spanning the transcription start site of all RP genes. Here we show that the Microprocessor complex, previously linked to the first step of processing microRNAs (miRNAs), coregulates RP expression by binding the TOP motif of nascent RP mRNAs and stimulating transcription elongation via resolution of DNA/RNA hybrids. Cell growth arrest triggers nuclear export and degradation of the Microprocessor protein Drosha by the E3 ubiquitin ligase Nedd4, accumulation of DNA/RNA hybrids at RP gene loci, decreased RP synthesis, and ribosome deficiency, hence synchronizing ribosome production with cell growth. Conditional deletion of Drosha in erythroid progenitors phenocopies human ribosomopathies, in which ribosomal insufficiency leads to anemia. Outlining a miRNA-independent role of the Microprocessor complex at the interphase between cell growth and ribosome biogenesis offers a new paradigm by which cells alter their protein biosynthetic capacity and cellular metabolism.in response to the change in cellular growth environment remains to be identified (Meyuhas and Kahan, 2015; Patursky-Polischuk et al., 2014).During transcription, a three-stranded nucleic acid structure known as an R-loop spontaneously forms(García-Muse and Aguilera, 2019). It is composed of a DNA/RNA hybrid (a single-stranded template DNA (ssDNA) hybridized with a nascent mRNA) and an associated non-template ssDNA (García-Muse and Aguilera, 2019;Sanz and Chédin, 2019;Sanz et al., 2016). R-loops are critical modulator of gene expression and DNA repair (García-Muse and Aguilera, 2019;Sanz and Chédin, 2019;Sanz et al., 2016), and their extended persistence during transcription is inhibitory to gene expression (Gowrishankar et al., 2013;Nudler, 2012). The abundance of R-loops is determined by the balance between its formation and resolution of DNA/RNA hybrids and various factors, including transcription factors, helicases, ribonucleases, topoisomerases, chromatin remodelers, proteins in DNA repair and RNA surveillance, have been identified to control R-loop homeostasis(García-Muse and Aguilera, 2019). Deregulation of R-loops, which results in aberrant gene expression and chromatin structure, increased DNA breaks, and genome instability, contributes to human disease, including neurological disorders and tumorigenesis (García-Muse and Aguilera, 2019;Groh and Gromak, 2014;Sanz et al., 2016).The Microprocessor complex comprises two core components, the ribonuclease (RNase) III Drosha and its cofactor Dgcr8. It is essential for the biogenesis of most microRNAs (miRNAs), short RNAs that repress gene expression by binding to messenger RNAs and targeting them for degradation and/or preventing their translation (Han et al., 2004;Siomi and Siomi, 2010). The Microprocessor localizes predom...

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Autogenous Control of 5′TOP mRNA Stability by 40S Ribosomes

Cited by 93 publications

References 46 publications

SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies

SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies

LARP1 facilitates translational recovery after amino acid refeeding by preserving long poly(A)-tailed TOP mRNAs

Control of ribosomal protein synthesis by Microprocessor complex

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