bims-micpro 2025-09-14 papers

Genes Dev. 2025 Sep 10.

Multiple human enhancer RNAs contain long translated open reading frames.

Pavel A Vlasov, Koichi Ogami, Elizabeth Valenzuela, Risa Karakida Kawaguchi, Marko Jovanovic, James L Manley.

Enhancer RNAs (eRNAs) are transcribed by RNA polymerase IIduring enhancer activation but are typically rapidly degraded in the nucleus. During states of reduced RNA surveillance, however, eRNAs and other similar "noncoding" RNAs (including, e.g., upstream antisense RNAs) are stabilized, and some are exported to the cytoplasm and can even be found on polysomes. Here, we report unexpectedly that ∼12% of human intergenic eRNAs contain long open reading frames (>300 nt), many of which can be actively translated, as determined by ribosome profiling, and produce proteins that accumulate in cells, as shown by mass spectrometry (MS) data. Focusing on the largest of the encoded proteins, which we designated as eORFs, which can be up to ∼45 kDa, we found, remarkably, that most are highly basic, with pIs >11.5. This unusual chemistry reflects a striking overabundance of arginine residues and occurs despite a relative paucity of lysines. Exogenous expression of the 10 largest eORFs revealed that they accumulate stably in cells as full-length proteins, and most localize to the nucleus and associate with chromatin. Identification of interacting proteins by MS suggested possible roles for these proteins in several nuclear processes. The eORFs studied are well conserved among primates, though they are largely absent from other mammals. Notably, several contain human-specific C-terminal extensions and display properties suggestive of de novo gene birth. In summary, we have discovered that a fraction of human eRNAs can function as mRNAs, revealing a new and unexpected role for these transcripts.

Keywords: RNA; enhancers; translation

DOI: https://doi.org/10.1101/gad.352944.125

Mutat Res Rev Mutat Res. 2025 Sep 09. pii: S1383-5742(25)00033-X. [Epub ahead of print]796 108562

Mechanistic roles of long non-coding RNAs in DNA damage response and genome stability.

Li Wu, Lingli Wang, Jingyu Hou, Zhengping Shao, Jun Yang, Xiangwei Gao.

To maintain genomic stability, cells have evolved complex mechanisms collectively known as the DNA damage response (DDR), which includes DNA repair, cell cycle checkpoints, apoptosis, and gene expression regulation. Recent studies have revealed that long non-coding RNAs (lncRNAs) are pivotal regulators of the DDR. Beyond their established roles in recruiting repair proteins and modulating gene expression, emerging evidence highlights two particularly intriguing functions. First, some lncRNAs contain small open reading frames (sORFs) encoding functional micropeptides that actively participate in DDR pathways. Second, lncRNAs regulate R-loop homeostasis, a key mechanism for preserving genome integrity. Together, these findings expand our understanding of lncRNAs in the DDR, positioning them as both key mechanistic players and promising therapeutic targets.

Keywords: DNA damage response; Long noncoding RNA; Micropeptides; R-loop; SORF

DOI: https://doi.org/10.1016/j.mrrev.2025.108562

mSphere. 2025 Sep 08. e0034325

Investigation of the global translational response to oxidative stress in the model archaeon Haloferax volcanii reveals untranslated small RNAs with ribosome occupancy.

Emma Dallon, Haley M Moran, Sadhana R Chidambaran, Arman Kian, Betty Y H Huang, Stephen D Fried, Jocelyne DiRuggiero.

Oxidative stress induces a wide range of cellular damage, often causing disease and cell death. While many organisms are susceptible to the effects of oxidative stress, haloarchaea have adapted to be highly resistant. Several aspects of the haloarchaeal oxidative stress response have been characterized; however, little is known about the impacts of oxidative stress at the translation level. Using the model archaeon Haloferax volcanii, we performed RNA-seq and ribosome profiling (Ribo-seq) to characterize the global translation landscape during oxidative stress. We identified 281 genes with differential translation efficiency (TE). Downregulated genes were enriched in ribosomal and translation proteins, in addition to peroxidases and genes involved in the TCA cycle. We also identified 42 small noncoding RNAs (sRNAs) with ribosome occupancy. Size distributions of ribosome footprints revealed distinct patterns for coding and noncoding genes, with 12 sRNAs matching the pattern of coding genes, and mass spectrometry confirming the presence of seven small proteins encoded by these sRNAs. However, the majority of sRNAs with ribosome occupancy had no evidence of coding potential. Of these ribosome-associated sRNAs, 12 had differential ribosome occupancy or TE during oxidative stress, suggesting that they may play a regulatory role during the oxidative stress response. Our findings on ribosomal regulation during oxidative stress, coupled with potential roles for ribosome-associated noncoding sRNAs and sRNA-derived small proteins in H. volcanii, revealed additional regulatory layers and underscored the multifaceted architecture of stress-responsive regulatory networks.IMPORTANCEArchaea are found in diverse environments, including as members of the human microbiome, and are known to play essential ecological roles in major geochemical cycles. The study of archaeal biology has expanded our understanding of the evolution of eukaryotes, uncovered novel biological systems, and revealed new opportunities for applications in biotechnology and bioremediation. Many archaeal systems, however, remain poorly characterized. Using Haloferax volcanii as a model, we investigated the global translation landscape during oxidative stress. Our findings expand current knowledge of translational regulation in archaea and further illustrate the complexity of stress-responsive gene regulation.

Keywords: archaea; ribosome profiling; small RNAs; stress response; translational control

DOI: https://doi.org/10.1128/msphere.00343-25

J Bacteriol. 2025 Sep 08. e0025525

Translational coupling of neighboring genes in prokaryotes.

Kerry M Brown, Joseph T Wade.

Prokaryotic genomes are gene-dense, so genes in the same orientation are often separated by short intergenic sequences or even overlap. Many mechanisms of regulation depend on open reading frames (ORFs) being spatially close to one another. Here, we describe one such mechanism, translational coupling, where translation of one gene promotes translation of a co-oriented neighboring gene. Translational coupling has been observed across the prokaryotic kingdom. Coupling is most efficient when the intergenic distance between ORFs is small. Coupling efficiency is influenced by RNA secondary structure, the presence of a Shine-Dalgarno (SD) sequence, and potentially by other cis-acting elements. While the mechanism of translational coupling has not been firmly established, two models have been proposed. In the RNA unfolding model, translation of the upstream gene in a pair disrupts inhibitory RNA secondary structure around the start codon of the downstream gene. Alternatively, the reinitiation model proposes that the same ribosome-either the 30S or complete 70S-translates both genes in a coupled pair. We describe evidence in support of each model, and we discuss the functional implications of translational coupling.

Keywords: translation; translational coupling

DOI: https://doi.org/10.1128/jb.00255-25

Cancers (Basel). 2025 Sep 07. pii: 2932. [Epub ahead of print]17(17):

A Novel Nuclear-Localized Micropeptide, MP60, Promotes Hepatocellular Carcinoma Progression via the Epithelial-Mesenchymal Transition.

Chencheng Li, Xiu Hong, Sarra Setrerrahmane, Xiaoyi Sun, Xue Zhang, Hanmei Xu.

Background: Micropeptides, encoded by non-coding RNAs, play a pivotal role in various cellular functions. While several micropeptides have already been linked to HCC, their roles remain incompletely understood. Our study identifies MP60, a conserved micropeptide strongly associated with HCC progression. Methods and Results: By analyzing The Cancer Genome Atlas (TCGA) dataset, we assessed the coding potential of long non-coding RNAs (lncRNAs) with significant expression changes in HCC. Our findings reveal that ENST0000614292, a transcript of LINC01138, exhibited the highest coding potential, encoding a putative 60-amino-acid micropeptide, which we have named MP60 and confirmed the expression of MP60 in HCC tissues, with a nuclear localization. MP60 directly interacts with RNA-binding motif protein 10 (RBM10) and downregulates its expression. Additionally, MP60 modulates EMT. Functional analyses demonstrated that MP60 promotes cellular proliferation and migration, while reducing cellular adhesion, translated by enhanced tumorigenesis in vivo. Notably, MP60 expression is markedly increased in HCC tissues and is associated with a poorer prognosis. Conclusions: These findings identify MP60 as a potential biomarker and therapeutic target in HCC, linking its oncogenic effects to EMT modulation and tumor progression.

Keywords: EMT; HCC; MP60; RBM10; micropeptides

DOI: https://doi.org/10.3390/cancers17172932

Biochem Soc Trans. 2025 Sep 12. pii: BST20253024. [Epub ahead of print]

The impact of ribosome association on lncRNA stability: a new layer of post-transcriptional control?

Courteney K Pienaar, Benjamin P Towler, Sarah F Newbury.

Long non-coding RNAs (lncRNAs) play crucial roles in cellular processes; however, the mechanisms controlling their stability are not well understood. Since the appropriate levels of lncRNAs in cells are required to carry out their functions, it is critical that their degradation is tightly controlled. Extensive research has shown that translation and degradation of messenger RNAs (mRNAs) are intricately linked, with repression of translation usually leading to degradation of the RNA. Recently, evidence has emerged to suggest that translation may also affect lncRNA stability. Ribosome engagement may stabilise lncRNAs by protecting them from nucleases or by promoting their degradation via ribosome-associated decay pathways such as nonsense-mediated decay. In this review, we first highlight specific human diseases that result from misregulation of lncRNA stability. We then explore the mechanisms underlying ribosome association and lncRNA stability, drawing comparisons with canonical mRNA mechanisms and highlighting emerging hypotheses that may be particularly relevant to lncRNAs. We also discuss how advanced techniques such as ribosome profiling can be applied to investigate whether lncRNAs are translated. Finally, we suggest future strategies to aid further understanding of lncRNA stability and its relationship with development and disease. Understanding the dynamic relationship between translation and lncRNA decay offers broad implications for RNA biology and provides new insights into the regulation of lncRNAs in both cellular and disease contexts.

Keywords: RNA stability; RNA turnover; long non-coding RNA; nonsense-mediated decay; smORFs; translation

DOI: https://doi.org/10.1042/BST20253024