Secondary structures in RNA synthesis, splicing and translation

Georgakopoulos-Soares, Ilias; Parada, Guillermo E.; Hemberg, Martin

doi:10.1016/j.csbj.2022.05.041

Cited by 32 publications

(25 citation statements)

References 272 publications

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“…As Figure 8 shows, although tRNA was previously thought to be a key contributor to translational speed, RandomRibo supports more recent studies showing that it is not as important in determining final ribosome velocity [18]. On the overall transcriptome level, both RNA Secondary Structure (RSS) and resistive electrostatic force are negatively correlated to final ribosome speed for the ramp codons 50 to 300 (R = −0.175, p = 5.52e-03; R = −0.276, p = 9.26e-06), corroborating previous data and explanations stating that secondary structures form barriers to ribosomes and positive charges slow down movement [21,22,16]. Therefore, RandomRibo can identify not only significant but scientifically consistent translation velocity determinants.…”

Section: Translation Elongation Velocity Determinants Found By Random...supporting

confidence: 85%

“…Ribosome profiling data, or Ribo-seq, is an essential tool for translation velocity determinant analysis [18]; when combined with high-throughput sequencing, this experimental protocol provides a snapshot of all actively translating ribosomes in a cell with positional information at single nucleotide resolution [6]. Using Ribo-seq data, previous studies have identified codon-specific dwell time [19,20], mRNA secondary structures [21,22], and nascent chain interactions with the ribosome exit tunnel [16,23] as key determinants of translational speed. Earlier approaches include techniques such as the inhomogeneous l-TASEP [18] for velocity calculation and the least-squares linear regression model [18,24] for determinant identification.…”

Section: Introductionmentioning

confidence: 99%

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RandomRibo: A Novel Tool for Transcript-Level Translation Elongation Velocity Determinant Identification at Single Codon Resolution

Parulekar-Martins¹

2022

Preprint

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Cells have evolved the process of translational regulation to rapidly fine-tune protein expression to suit intracellular needs. Ribosome velocity during translation elongation is a key contributor to typical protein expression, as abnormal regulation of it can give rise to disease states. Ribosomes travel along mRNA transcripts with varying speeds, with regions of high movement to increase efficiency as well as pause site regions to allow for processes such as co-translational folding. Having a comprehensive understanding of why ribosomal movement undergoes such positional fluctuation gives researchers critical, molecular-level insight into disease states. However, previous methods cannot offer precise information at the single transcript level due to the high amounts of noise present in Ribo-seq data and simple measures of determinants, rendering them unable to analyze a variety of disease states affecting the translation of specific genes. In this study, I present the software RandomRibo, the first computational tool to identify translation velocity determinants for individual transcripts by incorporating (1) Bayesian wavelet thresholding with double exponential priors to denoise ribosome profiling data, (2) nascent chain alpha helix propensity and electrostatic force algorithms to better model interactions with the ribosome exit tunnel, and (3) Random Forest Regression models to capture the non-linear relationships between translation velocity and its determinants. I demonstrate RandomRibo’s capabilities by applying its algorithms to different cell lines and cellular states to corroborate previous observations and establish novel hypotheses regarding the mechanisms of SARS-CoV-2 Nonstructural protein 1 (Nsp1).

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Section: Translation Elongation Velocity Determinants Found By Random...supporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

RandomRibo: A Novel Tool for Transcript-Level Translation Elongation Velocity Determinant Identification at Single Codon Resolution

Parulekar-Martins¹

2022

Preprint

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“…Both of these features can lead to the formation of the inverted repeat and secondary structure, i.e., hairpin loop and Internal Ribosome Entry Sites (IRES)(34). The formation of these secondary structures benefits of host-virus interaction, i.e., viral RNA synthesis, splicing (34, 35), and host genome integration (36).…”

Section: Discussionmentioning

confidence: 99%

Piscichuviral encephalitis in marine and freshwater chelonians: first evidence of jingchuviral disease

Laovechprasit

Young

Stacy

et al. 2023

Preprint

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Chuviruses (family Chuviridae), which are in the recently discovered order Jingchuvirales, were first identified in arthropods in 2015 and have been detected through metagenomics in numerous invertebrates, but only a few vertebrates. With only few metagenomically based detections in vertebrates, their replication competency in vertebrates remained questioned, let alone their pathological significance. This study identified three novel chuviruses as the etiology of lymphocytic meningoencephalomyelitis in three wild aquatic turtles: an alligator snapping turtle (Macrochelys sp.), a Kemps ridley turtle (Lepidochelys kempii), and a loggerhead turtle (Caretta caretta). The application of random, deep sequencing successfully assembled the complete snapping turtle chuvirus-1 [STCV-1], Kemps ridley turtle chuvirus-1 [KTCV-1] genome, and loggerhead turtle chuvirus-1 [LTCV-1]) genome. The STCV-1 and KTCV-1 sequences were used to create custom RNAscope probes for in situ hybridization, which confirmed STCV-1, KTCV-1, and LTCV-1 (cross reactivity to the KTCV-1 probe) RNA within the inflamed region of the brain and spinal cord. STCV-1 and KTCV-1 were isolated on several turtle-origin cell lines. Phylogenetic analysis illustrated that all three viruses clustered with other vertebrate chuviruses, all within the genus Piscichuvirus. With more than 91% pairwise amino acid identity of the polymerase proteins, STCV-1, KTCV-1, and LTCV-1 belong to the same novel species, putatively named Piscichuvirus testudinae. This study demonstrates the first in situ evidence of chuviral pathogenicity in animals and only the second instance of jingchuviral isolation. The association of these chuviruses in three different chelonians with neurologic disease suggests the possibility that chuviruses are a significant, previously unrecognized cause of lymphocytic meningoencephalomyelitis in freshwater and marine turtles. Additional studies of these viruses are needed to elucidate their role in chelonians and the possibility of related viruses in other related hosts.

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“…No direct HMGB‐mediated in vivo splicing mechanism has been demonstrated to date. Thus, non‐HMGB dual DNA and RNA binding proteins that impact splicing and other known splicing mechanisms are used to infer potential HMGB splicing mechanisms such as by modifying nascent RNA structure or the ability to form splicing complexes (Auboeuf et al, 2005; Georgakopoulos‐Soares et al, 2022; Han et al, 2017; Pandit et al, 2008; Rambout & Maquat, 2020; Saha et al, 2020; Scharfen & Neugebauer, 2021; Tang et al, 2021). As HMGBs likely interact with nascent RNA and may change the structure of RNA, it is possible that HMGBs direct manipulation of nascent RNA structure and/or the steric blocking or recruitment of splicing factors could alter splicing outcomes (Figure 6a–c).…”

Section: Hmgbs Interactions With Rna Impact Hmgb Cell Biologymentioning

confidence: 99%

“…As HMGBs likely interact with nascent RNA and may change the structure of RNA, it is possible that HMGBs direct manipulation of nascent RNA structure and/or the steric blocking or recruitment of splicing factors could alter splicing outcomes (Figure 6a–c). Sox family proteins, HMGB1, HMGB3, and other HMGBs all bind stem‐loop RNAs which are common RNA elements known to act as protein binding hubs during RNA processing, including splicing decisions (Georgakopoulos‐Soares et al, 2022; Kralovicova et al, 2015; Saha et al, 2020; Tang et al, 2021). Further, Sox6 appears to be important for spliceosome assembly.…”

Section: Hmgbs Interactions With Rna Impact Hmgb Cell Biologymentioning

confidence: 99%

TheDNAbinding high mobility group box protein family functionally bindsRNA

et al. 2023

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Nucleic acid binding proteins regulate transcription, splicing, RNA stability, RNA localization, and translation, together tailoring gene expression in response to stimuli. Upon discovery, these proteins are typically classified as either DNA or RNA binding as defined by their in vivo functions; however, recent evidence suggests dual DNA and RNA binding by many of these proteins. High mobility group box (HMGB) proteins have a DNA binding HMGB domain, act as transcription factors and chromatin remodeling proteins, and are increasingly understood to interact with RNA as means to regulate gene expression. Herein, multiple layers of evidence that the HMGB family are dual DNA and RNA binding proteins is comprehensively reviewed. For example, HMGB proteins directly interact with RNA in vitro and in vivo, are localized to RNP granules involved in RNA processing, and their protein interactors are enriched in RNA binding proteins involved in RNA metabolism. Importantly, in cell‐based systems, HMGB–RNA interactions facilitate protein–protein interactions, impact splicing outcomes, and modify HMGB protein genomic or cellular localization. Misregulation of these HMGB–RNA interactions are also likely involved in human disease. This review brings to light that as a family, HMGB proteins are likely to bind RNA which is essential to HMGB protein biology.This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications

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Secondary structures in RNA synthesis, splicing and translation

Cited by 32 publications

References 272 publications

RandomRibo: A Novel Tool for Transcript-Level Translation Elongation Velocity Determinant Identification at Single Codon Resolution

RandomRibo: A Novel Tool for Transcript-Level Translation Elongation Velocity Determinant Identification at Single Codon Resolution

Piscichuviral encephalitis in marine and freshwater chelonians: first evidence of jingchuviral disease

TheDNAbinding high mobility group box protein family functionally bindsRNA

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