Mammalian RNA switches: Molecular rheostats in gene regulation, disease, and medicine

Subbaiah, Kadiam C Venkata; Hedaya, Omar; Wu, Jiangbin; Jiang, Feng; Yao, Peng

doi:10.1016/j.csbj.2019.10.001

Cited by 19 publications

(16 citation statements)

References 132 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This model couples TPP and Mg 2+ binding to both short-timescale configurational changes in the sensor helices and long-timescale switch helix base pairing in the aptamer domain, bridging the gap between previously suggested fast and slow binding recognition and ON/OFF tuning mechanisms (Thore et al 2006;Haller et al 2013). These results also constitute direct evidence that some riboswitches function more as rheostats or dimmers in which ligand binding does not correlate 1:1 with ON/OFF switching, rather than as discrete ON/OFF switches, as suggested by others Venkata Subbaiah et al 2019). We propose that such rheostatic tuning could allow for fast response times for regulation of TPP concentrations in cells.…”

Section: Discussionsupporting

confidence: 77%

Ensemble switching unveils a kinetic rheostat mechanism of the eukaryotic thiamine pyrophosphate riboswitch

Saikia

Godar

et al. 2021

RNA

View full text Add to dashboard Cite

Thiamine pyrophosphate (TPP) riboswitches regulate thiamine metabolism by inhibiting the translation of enzymes essential to thiamine synthesis pathways upon binding to thiamine pyrophosphate in cells across all domains of life. Recent work on the Arabidopsis thaliana TPP riboswitch suggests a multi-step TPP binding process involving multiple riboswitch configurational ensembles and Mg 2+ dependence underlies the mechanism of TPP recognition and subsequent transition to the expression-inhibiting state of the aptamer domain followed by changes in the expression platform. However, details of the relationship between TPP riboswitch conformational changes and interactions with TPP and Mg 2+ in the aptamer domain constituting this mechanism are unknown. Therefore, we integrated single-molecule multiparameter fluorescence and force spectroscopy with atomistic molecular dynamics simulations and found that conformational transitions within the aptamer domain's sensor helices associated with TPP and Mg 2+ ligand binding occurred between at least five different ensembles on timescales ranging from µs to ms. These dynamics are orders of magnitude faster than the ten second-timescale folding kinetics associated with expression-state switching in the switch helix. Together, our results show that a TPP and Mg 2+ dependent mechanism determines dynamic configurational state ensemble switching of the aptamer domain's sensor helices that regulate the switch helix's stability, which ultimately may lead to the expressioninhibiting state of the riboswitch. Additionally, we propose that two pathways exist for ligand recognition and that this mechanism underlies a kinetic rheostat-like behavior of the Arabidopsis thaliana TPP riboswitch.

show abstract

Section: Discussionsupporting

confidence: 77%

Ensemble switching unveils a kinetic rheostat mechanism of the eukaryotic thiamine pyrophosphate riboswitch

Saikia

Godar

et al. 2021

RNA

View full text Add to dashboard Cite

show abstract

“…(iii) RNA control of SLN transcription and translation in horse muscle. Micro-RNAs control transcription and translation of key targets (i.e., mRNAs, lncRNAs, and proteins) in numerous organisms and cell types [ 128 , 129 , 130 ]. Thus, it is possible that micro-RNAs in horse gluteal muscle act to shut down SLN peptide production from the high-level of SLN transcript production.…”

Section: Discussionmentioning

confidence: 99%

Sarcolipin Exhibits Abundant RNA Transcription and Minimal Protein Expression in Horse Gluteal Muscle

Autry

Karim

Perumbakkam

et al. 2020

Veterinary Sciences

View full text Add to dashboard Cite

Ca2+ regulation in equine muscle is important for horse performance, yet little is known about this species-specific regulation. We reported recently that horse encode unique gene and protein sequences for the sarcoplasmic reticulum (SR) Ca2+-transporting ATPase (SERCA) and the regulatory subunit sarcolipin (SLN). Here we quantified gene transcription and protein expression of SERCA and its inhibitory peptides in horse gluteus, as compared to commonly-studied rabbit skeletal muscle. RNA sequencing and protein immunoblotting determined that horse gluteus expresses the ATP2A1 gene (SERCA1) as the predominant SR Ca2+-ATPase isoform and the SLN gene as the most-abundant SERCA inhibitory peptide, as also found in rabbit skeletal muscle. Equine muscle expresses an insignificant level of phospholamban (PLN), another key SERCA inhibitory peptide expressed commonly in a variety of mammalian striated muscles. Surprisingly in horse, the RNA transcript ratio of SLN-to-ATP2A1 is an order of magnitude higher than in rabbit, while the corresponding protein expression ratio is an order of magnitude lower than in rabbit. Thus, SLN is not efficiently translated or maintained as a stable protein in horse muscle, suggesting a non-coding role for supra-abundant SLN mRNA. We propose that the lack of SLN and PLN inhibition of SERCA activity in equine muscle is an evolutionary adaptation that potentiates Ca2+ cycling and muscle contractility in a prey species domestically selected for speed.

show abstract

“…mRNA translation is one of the posttranscriptional processes affected by RBPs extensively (10). As the most energy-consuming and precisely regulated process in cells, translation is tightly controlled through cis-acting RNA elements such as terminal oligopyrimidine (TOP) motifs and CA-rich elements (11)(12)(13) and through trans-acting factors such as mRNA binding proteins (mRBPs) (2,10,14). The latter affects all steps in global or transcript-specific translation (10).…”

Section: Introductionmentioning

confidence: 99%

RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression

Jiang

Hedaya

Khor

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Accumulating evidence suggests that posttranscriptional control of gene expression, including RNA splicing, transport, modification, translation, and degradation, primarily relies on RNA binding proteins (RBPs). However, the functions of many RBPs remain understudied. Here, we characterized the function of a novel RBP, Proline-Rich Coiled-coil 2B (PRRC2B). Through photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and sequencing (PAR-CLIP-seq), we identified transcriptome-wide CU- or GA-rich PRRC2B binding sites around the translation initiation codon on a specific cohort of mRNAs in HEK293T cells. These mRNAs, including oncogenes and cell cycle regulators such asCCND2(cyclin D2), exhibited decreased translation upon PRRC2B knockdown as revealed by polysome-associated RNA-seq, resulting in reduced G1/S phase transition and cell proliferation. Antisense oligonucleotides blocking PRRC2B interactions withCCND2mRNA decreased its translation, thus inhibiting G1/S transition and cell proliferation. Mechanistically, PRRC2B interactome analysis revealed RNA-independent interactions with eukaryotic translation initiation factors 3 (eIF3) and 4G2 (eIF4G2). The interaction with translation initiation factors is essential for PRRC2B function since the eIF3/eIF4G2-interacting defective mutant, unlike wild-type PRRC2B, failed to rescue the translation deficiency or cell proliferation inhibition caused by PRRC2B knockdown. Altogether, our findings reveal that PRRC2B is essential for efficient translation of specific proteins required for cell cycle progression and cell proliferation.

show abstract

Mammalian RNA switches: Molecular rheostats in gene regulation, disease, and medicine

Cited by 19 publications

References 132 publications

Ensemble switching unveils a kinetic rheostat mechanism of the eukaryotic thiamine pyrophosphate riboswitch

Ensemble switching unveils a kinetic rheostat mechanism of the eukaryotic thiamine pyrophosphate riboswitch

Sarcolipin Exhibits Abundant RNA Transcription and Minimal Protein Expression in Horse Gluteal Muscle

RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression

Contact Info

Product

Resources

About