Position-Dependent NMD Generates Diverse Protein Outcomes

DIS3L2 and nonsense-mediated decay: united to degrade.

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.

Signatures of nonsense-mediated mRNA decay but no evidence for transcriptional adaptation associated with protein-truncating variants in wild yeast diploids.

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.

Global Changes in Unproductive Splicing and NMD Efficiency in Tumors

The nonsense-mediated mRNA decay (NMD) pathway is a mRNA quality control mechanism which not only degrades deleterious transcripts but also orchestrates a large number of post-transcriptional regulatory programs through unproductive splicing. We have developed a robust metric derived from splicing quantification in the RNA-seq data to measure NMD efficiency at a sample level. We demonstrate that NMD efficiency varies substantially both between and within tissues, with the magnitude of the variation comparable to that observed upon knockdown of the core NMD factor UPF1. By analyzing TCGA cancer cohorts, we further show that, in many tumors, unproductive splicing events undergo coordinated changes towards either collective suppression or collective activation of NMD isoforms, which is indicative of global deregulation of the activity of the NMD pathway. Consistently, we observed a striking divergence of NMD efficiency in cancers from the tissue-specific baseline level, suggesting that tumors partially erase the NMD signature of their tissue of origin. The application of the developed metric to RNA-binding protein knockdowns made it possible to identify several novel potential regulators of NMD efficiency. In sum, this study provides a solid framework for quantifying NMD efficiency, describes its biological and clinical relevance, and opens new avenues for dissecting mechanisms of post-transcriptional gene expression regulation by the NMD pathway.

Nonsense-mediated mRNA decay as a gatekeeper of neoantigen expression: Bridging RNA surveillance and tumor immunotherapy

Nonsense-mediated mRNA decay and associated splicing patterns in neurodevelopmental disorders

Nonsense-mediated mRNA decay (NMD) is a basic post-transcriptional mechanism ensuring the fidelity of many biological processes including brain development. Together with alternative splicing, it regulates the inclusion of poison exons. NMD is involved in the control of multiple processes during brain development such as neural progenitor proliferation and differentiation, neuronal migration, axonal guidance, and synaptic plasticity. Under physiological conditions, this mechanism safeguards neuronal identity and the functional maturation of the brain. When disrupted, the consequences range from structural cerebral anomalies to cognitive impairment and epilepsy. This review examines NMD-mediated regulatory mechanisms across different stages of brain development. Special emphasis is placed on how dysfunction in NMD pathway components—specifically core degradation factors, the exon junction complex, and neuron-specific splicing regulators—underpins an extensive array of neurodevelopmental disorders (NDDs). Furthermore, we delineate the relationship between the position of a premature termination codon (PTC) within a transcript and the resulting molecular outcome. While the degradation of aberrant mRNAs often leads to haploinsufficiency, their escape from NMD might result in the accumulation of truncated proteins with dominant-negative effects, thereby causing specific clinical phenotypes in affected patients. Elucidating these mechanisms is essential for both the interpretation of variant pathogenicity and the development of targeted therapeutic strategies.

Activity-dependent ribosome profiling reveals the landscape of canonical and non-canonical translation in brain tissue

A ribosome tagging and purification strategy is developed that bypasses the prolonged turnover of ribosomal proteins, enabling ribosome profiling with one-hour temporal resolution after neural stimulation, and uncovered previously unknown activity-dependent alternative translation with functional implication, such as the uORF of Egr1.