bims-micpro 2023-08-20 papers

Issue of 2023‒08‒20
three papers selected by
Thomas Farid Martínez, University of California, Irvine

Mol Cell Proteomics. 2023 Aug 10. pii: S1535-9476(23)00142-1. [Epub ahead of print] 100631

What can Ribo-seq, immunopeptidomics, and proteomics tell us about the non-canonical proteome?

John R Prensner, Jennifer G Abelin, Leron W Kok, Karl R Clauser, Jonathan M Mudge, Jorge Ruiz-Orera, Michal Bassani-Sternberg, Robert L Moritz, Eric W Deutsch, Sebastiaan van Heesch.

Ribosome profiling (Ribo-seq) has proven transformative for our understanding of the human genome and proteome by illuminating thousands of non-canonical sites of ribosome translation outside of the currently annotated coding sequences (CDSs). A conservative estimate suggests that at least 7,000 non-canonical open reading frames (ORFs) are translated, which, at first glance, has the potential to expand the number of human protein-coding sequences by 30%, from ∼19,500 annotated CDSs to over 26,000. Yet, additional scrutiny of these ORFs has raised numerous questions about what fraction of them truly produce a protein product and what fraction of those can be understood as proteins according to conventional understanding of the term. Adding further complication is the fact that published estimates of non-canonical ORFs vary widely by around 30-fold, from several thousand to several hundred thousand. The summation of this research has left the genomics and proteomics communities both excited by the prospect of new coding regions in the human genome, but searching for guidance on how to proceed. Here, we discuss the current state of non-canonical ORF research, databases, and interpretation, focusing on how to assess whether a given ORF can be said to be "protein-coding".

Keywords: Ribo-seq; immunopeptidomics; mass spectrometry; microprotein; non-canonical open reading frame

DOI: https://doi.org/10.1016/j.mcpro.2023.100631

Plant Sci. 2023 Aug 14. pii: S0168-9452(23)00239-X. [Epub ahead of print]335 111822

Translation initiation at AUG and non-AUG triplets in plants.

Jhen-Cheng Fang, Ming-Jung Liu.

In plants and other eukaryotes, precise selection of translation initiation site (TIS) on mRNAs shapes the proteome in response to cellular events or environmental cues. The canonical translation of mRNAs initiates at a 5' proximal AUG codon in a favorable context. However, the coding and non-coding regions of plant genomes contain numerous unannotated alternative AUG and non-AUG TISs. Determining how and why these unexpected and prevalent TISs are activated in plants has emerged as an exciting research area. In this review, we focus on the selection of plant TISs and highlight studies that revealed previously unannotated TISs used in vivo via comparative genomics and genome-wide profiling of ribosome positioning and protein N-terminal ends. The biological signatures of non-AUG TIS-initiated open reading frames (ORFs) in plants are also discussed. We describe what is understood about cis-regulatory RNA elements and trans-acting eukaryotic initiation factors (eIFs) in the site selection for translation initiation by featuring the findings in plants along with supporting findings in non-plant species. The prevalent, unannotated TISs provide a hidden reservoir of ORFs that likely help reshape plant proteomes in response to developmental or environmental cues. These findings underscore the importance of understanding the mechanistic basis of TIS selection to functionally annotate plant genomes, especially for crops with large genomes.

Keywords: Alternative translation initiation sites; Gene regulation; Non-AUG start codons

DOI: https://doi.org/10.1016/j.plantsci.2023.111822

Balkan J Med Genet. 2023 Jul;26(1): 51-56

Androgen Insensitivity Syndrome DUE to Non-Coding Variation in the Androgen Receptor Gene: Review of the Literature and Case Report of a Patient with Mosaic c.-547C>T Variant.

P Noveski, T Plaseski, M Dimitrovska, D Plaseska-Karanfilska.

Sexual development (SD) is a complex process with strict spatiotemporal regulation of gene expression. Despite advancements in molecular diagnostics, disorders of sexual development (DSD) have a diagnostic rate of ~50%. Androgen insensitivity syndrome (AIS) represents the most common form of 46,XY DSD, with a spectrum of defects in androgen action. Considering the importance of very strict regulation of the SD, it is reasonable to assume that the genetic cause for proportion of the DSD lies in the non-coding part of the genome that regulates proper gene functioning. Here we present a patient with partial AIS (PAIS) due to a mosaic de novo c.-547C>T pathogenic variant in the 5'UTR of androgen receptor (AR) gene. The same mutation was previously described as inherited, in two unrelated patients with complete AIS (CAIS). Thus, our case further confirms the previous findings that variable gene expressivity could be attributed to mosaicism. Mutations in 5'UTR could create new upstream open reading frames (uORFs) or could disrupt the existing one. A recent systematic genome-wide study identified AR as a member of a subset of genes where modifications of uORFs represents an important disease mechanism. Only a small number of studies are reporting non-coding mutations in the AR gene and our case emphasizes the importance of molecular testing of the entire AR locus in AIS patients. The introduction of new methods for comprehensive molecular testing in routine genetic diagnosis, accompanied with new tools for in sillico analysis could improve the genetic diagnosis of AIS, and DSD in general.

Keywords: 5′UTR variant; Androgen insensitivity syndrome (AIS); mosaicism; non-coding variation; upstream open reading frames (uORFs)

DOI: https://doi.org/10.2478/bjmg-2023-0012