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UniProt release 2017_09

Published September 27, 2017

Headline

Protein translation goes round in circles

Covalently closed circular RNA molecules (circRNAs) were observed over 40 years ago in viruses. Later on, they were discovered in non-infected eukaryotes. In 1993, Capel et al. reported the existence of unusual circular Sry transcripts in mouse testis where they represented the most abundant transcript. These peculiar RNA species have generally been considered to be of low abundance, likely representing errors in splicing. Recent studies have shown however that they may actually be quite numerous and produced by thousands of genes. In addition, they are evolutionarily conserved. CircRNAs are generated by the spliceosome via backsplicing, a process in which the 3’-end of an exon is covalently linked to the 5’-end of an upstream exon. As a result, they lack typical mRNA terminal structures, such as 5’ cap and polyA tail. This feature leads to exonuclease resistance, allowing circRNAs to escape from normal RNA turnover processes.

The physiological functions of circRNAs have not yet been extensively explored. Some have been shown to act as microRNA sponges. They can also function as platforms for protein interaction. For instance, circ-FOXO3 represses cell cycle progression by binding to the cell cycle proteins CDK2 and CDKN1A (p21), resulting in the formation of a ternary complex. Circ-MBL/MBNL1 binds to the RNA-binding MBNL1 protein and regulates gene expression by competing with pre-mRNA linear splicing of its linear counterpart.

At this point, you may wonder why UniProtKB, a protein resource, is interested in circRNAs. Most circRNAs originate from protein-coding genes and contain complete exons. In theory they could be translated, but there has been no direct evidence for in vivo translation of endogenous transcripts, and they were classified as non-coding RNAs.

A major breakthrough came from a study done in human and mouse muscles published last April. Muscles not only produce thousands of circular splicing events, but the expression of circRNAs is also differentially regulated during myoblast differentiation. Among them, circ-ZNF609, a transcript that originates from the circularization of the first coding exon of ZNF609 gene, is down-regulated during myogenesis. Circ-ZNF609 contains the initiation codon of the linear ZNF609 transcript, a putative 753-nucleotide open reading frame and a STOP codon created 3 nucleotide after the splice junction by the circularization event with the upstream ZNF609 5’-UTR. In human myoblasts, the knockdown of circ-ZNF609, but not that of its linear transcript, reduces cell proliferation by about 80%, suggesting a specific role in the regulation of myoblast proliferation. Circ-ZNF609 transcripts are located in the cytoplasm where they are associated with heavy polysomes. They are translated in a cap-independent manner, though less efficiently than their linear counterparts and produce a new 250-amino acid long ZNF609 isoform, both in human and mouse cells. The translation is driven by an internal ribosomal entry site (IRES) located within the 5’-UTR. In vivo translation of at least some circRNAs was confirmed in Drosophila in the same issue of Molecular Cell.

In June 1963, Sidney Brenner wrote to Max Perutz: ‘It is now widely realized that nearly all the ‘classical’ problems of molecular biology have either been solved or will be solved in the next decade.’ One could think that the process in which genetic information is transcribed and processed into functional RNAs would be such ‘classical’ problem, but it seems that there are still plenty of discoveries to be made in this field, for our greatest pleasure.

Human and mouse ZNF609 UniProtKB/Swiss-Prot entries have been updated and the new isoforms encoded by circ-ZNF609 integrated, with the help of Dr. Legnini whom we want to sincerely thank. The revised entries are publicly available as of this release.

Cross-references to CORUM

Cross-references have been added to the CORUM database, a resource of manually annotated protein complexes from mammalian organisms.

CORUM is available at http://mips.helmholtz-muenchen.de/corum/

The format of the explicit links is:

Resource abbreviation CORUM
Resource identifier UniProtKB accession number

Example: P41182

Show all entries having a cross-reference to CORUM.

Text format

Example: P41182

DR   CORUM; P41182; -.

XML format

Example: P41182

<dbReference type="CORUM" id="P41182"/>

RDF format

Example: P41182

uniprot:P41182
  rdfs:seeAlso <http://purl.uniprot.org/corum/P41182> .
<http://purl.uniprot.org/corum/P41182> 
rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/CORUM> .

Changes to the controlled vocabulary of human diseases

New diseases:

Deleted diseases

  • Adrenocortical insufficiency, without ovarian defect

Changes in subcellular location controlled vocabulary

New subcellular location: