The new uORFdb: integrating literature, sequence, and variation data in a central hub for uORF research

Manske, Felix; Ogoniak, Lynn; Jürgens, Lara; Grundmann, Norbert; Makałowski, Wojciech; Wethmar, Klaus

doi:10.1093/nar/gkac899

Cited by 15 publications

(12 citation statements)

References 65 publications

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“…uORFs attenuate main ORF translation by multiple mechanisms: by the “first dibs” scheme of translation initiation, by ribosome dissociation at the uORF stop codon, by stalling-mediated mRNA decay, and by encoding regulatory peptides [ 4 , 127 , 128 , 129 ]. uORF-mediated repression is widespread across the mammalian transcriptome [ 130 , 131 , 132 ] and is associated with diseases and stress responses (reviewed in [ 133 , 134 , 135 , 136 ]). For example, the integrated stress response depletes pre-initiation complexes to specifically de-repress translation from uORF-containing mRNAs [ 137 , 138 , 139 ].…”

Section: Upstream Open Reading Framesmentioning

confidence: 99%

Host-like RNA Elements Regulate Virus Translation

Khan,

Fox

2024

Viruses

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Viruses are obligate, intracellular parasites that co-opt host cell machineries for propagation. Critical among these machineries are those that translate RNA into protein and their mechanisms of control. Most regulatory mechanisms effectuate their activity by targeting sequence or structural features at the RNA termini, i.e., at the 5′ or 3′ ends, including the untranslated regions (UTRs). Translation of most eukaryotic mRNAs is initiated by 5′ cap-dependent scanning. In contrast, many viruses initiate translation at internal RNA regions at internal ribosome entry sites (IRESs). Eukaryotic mRNAs often contain upstream open reading frames (uORFs) that permit condition-dependent control of downstream major ORFs. To offset genome compression and increase coding capacity, some viruses take advantage of out-of-frame overlapping uORFs (oORFs). Lacking the essential machinery of protein synthesis, for example, ribosomes and other translation factors, all viruses utilize the host apparatus to generate virus protein. In addition, some viruses exhibit RNA elements that bind host regulatory factors that are not essential components of the translation machinery. SARS-CoV-2 is a paradigm example of a virus taking advantage of multiple features of eukaryotic host translation control: the virus mimics the established human GAIT regulatory element and co-opts four host aminoacyl tRNA synthetases to form a stimulatory binding complex. Utilizing discontinuous transcription, the elements are present and identical in all SARS-CoV-2 subgenomic RNAs (and the genomic RNA). Thus, the virus exhibits a post-transcriptional regulon that improves upon analogous eukaryotic regulons, in which a family of functionally related mRNA targets contain elements that are structurally similar but lacking sequence identity. This “thrifty” virus strategy can be exploited against the virus since targeting the element can suppress the expression of all subgenomic RNAs as well as the genomic RNA. Other 3′ end viral elements include 3′-cap-independent translation elements (3′-CITEs) and 3′-tRNA-like structures. Elucidation of virus translation control elements, their binding proteins, and their mechanisms can lead to novel therapeutic approaches to reduce virus replication and pathogenicity.

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Section: Upstream Open Reading Framesmentioning

confidence: 99%

Host-like RNA Elements Regulate Virus Translation

Khan,

Fox

2024

Viruses

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“…The third, LncBook ( 14 ), a curated database of human lncRNAs, reports improved multi-omics annotations including, for the first time, any experimentally-supported small proteins that they encode. Two further databases focus on uORFs: uORFDB ( 15 ) returns and expands on its original literature focus to now cover, sequences and sequence variants across 13 eukaryotes, while the new Ribo_uORF ( 16 ) provides rich annotations of uORFs identified by ribosome profiling across six animal species. Elsewhere, popular returning databases include AnimalTFDB which doubles its content to cover 183 animals ( 17 ); mirDIP, the aggregative database of microRNA–target interactions ( 18 ) and UTRdb, the database of richly annotated 5′ and 3′ untranslated regions of mRNA ( 19 ).…”

Section: New and Updated Databasesmentioning

confidence: 99%

The 2023 Nucleic Acids Research Database Issue and the online molecular biology database collection

Rigden

Fernández

2023

Nucleic Acids Research

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The 2023 Nucleic Acids Research Database Issue contains 178 papers ranging across biology and related fields. There are 90 papers reporting on new databases and 82 updates from resources previously published in the Issue. Six more papers are updates from databases most recently published elsewhere. Major nucleic acid databases reporting updates include Genbank, ENA, ChIPBase, JASPAR, mirDIP and the Issue's first Breakthrough Article, NACDDB for Circular Dichroism data. Updates from BMRB and RCSB cover experimental protein structural data while AlphaFold 2 computational structure predictions feature widely. STRING and REBASE are stand-out updates in the signalling and enzymes section. Immunology-related databases include CEDAR, the second Breakthrough Article, for cancer epitopes and receptors alongside returning IPD-IMGT/HLA and the new PGG.MHC. Genomics-related resources include Ensembl, GWAS Central and UCSC Genome Browser. Major returning databases for drugs and their targets include Open Targets, DrugCentral, CTD and Pubchem. The EMPIAR image archive appears in the Issue for the first time. The entire database Issue is freely available online on the Nucleic Acids Research website (https://academic.oup.com/nar). The NAR online Molecular Biology Database Collection has been updated, revisiting 463 entries, adding 92 new resources and eliminating 96 discontinued URLs so bringing the current total to 1764 databases. It is available at http://www.oxfordjournals.org/nar/database/c/.

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“…To get mRNA characteristics we used MANE Select set to select a single representative transcript for each protein-coding gene. uORF database uORFdb (Manske et al, 2023) was used to get number of ATG uORFs per mRNA.…”

Section: Analysis Of Sequencing Datamentioning

confidence: 99%

Perturbations in eIF3 subunit stoichiometry alter expression of ribosomal proteins and key components of the MAPK signaling pathways

Valášek

Herrmannová

Jelı́nek

et al. 2023

Preprint

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The MAPK cascade plays a key role in transducing extracellular signals into cellular responses. As such, it is unsurprisingly hyperactive in various cancers, primarily due to activating or loss-of-function mutations of its components. Various pathologies, including cancer, are also characterized by deregulated protein synthesis, where imbalanced expression of eIFs is not only a consequence of neoplasia but itself a major contributor to it. eIF3 stands out as the largest, multi-subunit complex with a modular assembly, where aberrant expression of one subunit generates only partially functional subcomplexes. Here, we knocked-down eIF3d, eIF3e and eIF3h in HeLa cells and investigated their impact on differential gene expression by Ribo-Seq. Knock-downs of eIF3d and eIF3e activated the MAPK/ERK1/2 signaling despite reduced protein levels of its multiple components. Depletion of eIF3e and partially eIF3d also increased expression of ribosomal proteins, implicating eIF3 in controlling balanced production of mature ribosomes. Moreover, intact eIF3 also regulates the expression of the proto-oncogene MDM2 and the transcription factor ATF4, both containing short uORFs. eIF3 thus exerts specific translational control over signaling and stress-related transcripts.

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The new uORFdb: integrating literature, sequence, and variation data in a central hub for uORF research

Cited by 15 publications

References 65 publications

Host-like RNA Elements Regulate Virus Translation

Host-like RNA Elements Regulate Virus Translation

The 2023 Nucleic Acids Research Database Issue and the online molecular biology database collection

Perturbations in eIF3 subunit stoichiometry alter expression of ribosomal proteins and key components of the MAPK signaling pathways

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