Signatures of nonsense-mediated mRNA decay but no evidence for transcriptional adaptation associated with protein-truncating variants in wild yeast diploids.
Aug 2026· Molecular biology and evolution· 0 citations
Medicine
TL;DR
Overall, the findings suggest that TA is not a universal response to loss-of-function mutations in yeast, and the ability to resist specific transcriptomic ruptures would thus rely mostly on the general robustness of genetic networks.
Abstract
Transcriptional adaptation (TA) is a regulatory process in which loss or disruption of gene function caused by protein-truncating variants (PTVs) triggers compensatory changes in expression of the healthy allele or in expression of related genes. Nonsense-mediated mRNA decay (NMD), a conserved RNA surveillance pathway that degrades transcripts containing premature termination codons, is required to initiate this process. In natural yeast populations, PTV mutations occur relatively frequently, raising the question of whether and how their effects are mitigated. In this study, we investigated TA and NMD among PTVs occurring in natural yeast populations. We observed a strong reduction in the abundance of PTV-containing transcripts, suggesting efficient recognition and degradation of transcripts containing premature stop codons. However, despite evidence of this mRNA surveillance activity, we did not detect a clear signature of transcriptional adaptation. While compensation may still occur in specific contexts, particularly for dosage-sensitive genes, it does not appear to represent a general response to PTVs in yeast. The transcriptional deregulation caused by PTVs in natural isolates may be causing too little harm to favor the evolution or maintenance of complex mechanisms required for adequate compensation. The ability to resist specific transcriptomic ruptures would thus rely mostly on the general robustness of genetic networks. Overall, our findings suggest that TA is not a universal response to loss-of-function mutations in yeast.
Nonsense-mediated decay (NMD) is a vital RNA surveillance mechanism in eukaryotic cells that ensures mRNA quality and regulates gene expression. NMD targets mRNAs with premature translation-termination codons to prevent the production of potentially harmful truncated proteins. But NMD is also involved in modulating the expression of physiological mRNAs to maintain cellular homeostasis. This NMD function is particularly relevant to calibrate the cellular transcriptome in response to environmental signals and stress. Its conservation across eukaryotes highlights its essential role. When active, NMD promotes mRNA degradation involving exoribonucleases like XRN1 (5' to 3') and the exosome (3' to 5'). DIS3L2, an exosome-independent exonuclease that primarily targets substrates marked by the non-templated addition of uridine residues to the 3' end of RNA molecules by terminal uridylyl transferases, can also degrade some NMD substrates, especially those that underwent 3' end uridylation. This review explores DIS3L2's interaction with the NMD pathway (DIS3L2/NMD pathway) and the human disorders associated with a dysfunctional DIS3L2/NMD pathway. A better understanding of the interplay between NMD and DIS3L2 will certainly allow the development of novel treatments for disorders associated with an affected DIS3L2/NMD pathway.
Rafaela Lacerda, Miguel Carvalho, L. Romão· Journal of Molecular Biology· 1 citation
It is shown that PTC location critically determines not only NMD efficiency and its variability across cells, but also the spectrum of resulting protein products, including truncated proteins arising from premature termination, full-length proteins generated through translational readthrough, and N-terminally truncated isoforms produced by downstream reinitiation.
It is proposed that MraW modification of 16S rRNA enhances translation efficiency in general, and that specific transcripts have evolved structural features that fine-tune protein levels that may be prevalent in bacteria which exhibit uncoupled transcription and translation.
Zachory M. Park, Christina R. Savage, Amanda R. Decker-Farrell et al.· Cell Reports· 0 citations
The CRISPR strategy shows compelling evidence as a therapeutic approach targeting PE in cancer and other human diseases as well as the preferential advantages of CRISPR over the antisense technology recently developed targeting the PE of EZH2.
Transcriptional regulation of protein-coding genes is a hallmark of eukaryotic gene expression. Yet, a group of parasitic protists, trypanosomatids, appear to lack this capability. Here, we analyzed genomic, nascent transcriptomic, RNA polymerase occupancy and gene organization data to reconstruct the evolutionary origin and biological consequences of their unusual regulatory strategy. Across 59 Discoba protists, we show stepwise evolutionary erosion of conventional transcription regulation components in trypanosomatida lineage, including gene consolidation into polycistronic transcription units (PTUs), shortening of intra-PTU non-coding regions, and depletion of transcription factors and their enriched DNA-binding motifs. This transition was associated with near-constitutive expression of most genes, indicating broad loss of conditional gene expression. However, trypanosomatids retain some differential regulation at the PTU level, with >70% PTUs featuring significantly different nascent transcription than their neighbors or resident chromosomes. Moreover, gene expression is not uniform within PTUs: nascent transcription, translation efficiency, and protein abundance progressively decline with distance from the transcription start site. Consistent with this architecture-encoded regulatory logic, co-complex subunits and co-pathway enzymes preferentially occupy adjacent positions within PTUs despite each PTU’s overall functional heterogeneity. These findings reveal an evolutionary shift from gene-specific transcriptional regulation toward a regime where genome architecture becomes a regulator of gene expression.
Saurav Mallik, Meir Sylman, Moshe Kafri et al.· bioRxiv· 0 citations