bims-micpro 2024-11-03 papers

Gene. 2024 Oct 24. pii: S0378-1119(24)00900-4. [Epub ahead of print] 149019

Micropeptides derived from long non-coding RNAs: Computational analysis and functional roles in breast cancer and other diseases.

Saisai Chen, Mengru Liu, Weizhen Yi, Huagang Li, Qingsheng Yu.

Long non-coding RNAs (lncRNAs), once thought to be mere transcriptional noise, are now revealing a hidden code. Recent advancements like ribosome sequencing have unveiled that many lncRNAs harbor small open reading frames and can potentially encode functional micropeptides. Emerging research suggests these micropeptides, not the lncRNAs themselves, play crucial roles in regulating homeostasis, inflammation, metabolism, and especially in breast cancer progression. This review delves into the rapidly evolving computational tools used to predict and validate lncRNA-encoded micropeptides. We then explore the diverse functions and mechanisms of action of these micropeptides in breast cancer pathogenesis, with a focus on their roles in various species. Ultimately, this review aims to illuminate the functional landscape of lncRNA-encoded micropeptides and their potential as therapeutic targets in cancer.

Keywords: Cancer; Computational analysis; Long non-coding RNAs; Molecular Functions; Therapeutic Targets; micropeptides

DOI: https://doi.org/10.1016/j.gene.2024.149019

Trends Plant Sci. 2024 Oct 28. pii: S1360-1385(24)00273-5. [Epub ahead of print]

Engineering crop performance with upstream open reading frames.

Rui Mou, Ruixia Niu, Ruoying Yang, Guoyong Xu.

Plants intricately regulate the expression of protein-coding genes at multiple stages - including mRNA transcription, translation, decay, and protein degradation - to control growth, development, and responses to environmental challenges. Recent research highlights the importance of translational reprogramming as a pivotal mechanism in regulating gene expression across diverse physiological scenarios. This regulatory mechanism bears practical implications, particularly in bolstering crop productivity by manipulating RNA regulatory elements (RREs) to modulate heterologous gene expression through transgene and endogenous gene expression through gene editing. Here, we elucidate the potential of upstream open reading frames (uORFs), a prominent and stringent class of RREs, in optimizing crop performance, exemplifying the efficacy of translational control in enhancing agricultural yields.

Keywords: gene editing; genetic engineering; synthetic biology; transgene; translational control; upstream open reading frame

DOI: https://doi.org/10.1016/j.tplants.2024.10.005

bioRxiv. 2024 Oct 25. pii: 2024.10.22.619581. [Epub ahead of print]

Alternative transcripts recode human genes to express overlapping, frameshifted microproteins.

Haomiao Su, Samuel G Katz, Sarah A Slavoff.

Overlapping genes were thought to be essentially absent from the human genome until the discovery of abundant, frameshifted internal open reading frames (iORFs) nested within annotated protein coding sequences. However, it is currently unclear how many functional human iORFs exist and how they are expressed. We demonstrate that, in hundreds of cases, alternative transcript variants that bypass the start codon of annotated coding sequences (CDSs) can recode a human gene to express the iORF-encoded microprotein. While many human genes generate such non- coding alternative transcripts, they are poorly annotated. Here we develope a new analysis pipeline enabling the assignment of translated human iORFs to alternative transcripts, and provide long- read sequencing and molecular validation of their expression in dozens of cases. Finally, we demonstrate that a conserved DEDD2 iORF switches the function of this gene from pro- to anti- apoptotic. This work thus demonstrates that alternative transcript variants can broadly reprogram human genes to express frameshifted iORFs, revealing new levels of complexity in the human transcriptome and proteome.

DOI: https://doi.org/10.1101/2024.10.22.619581

Mol Cell. 2024 Oct 24. pii: S1097-2765(24)00826-8. [Epub ahead of print]

Senescence suppresses the integrated stress response and activates a stress-remodeled secretory phenotype.

Matthew J Payea, Showkat A Dar, Carlos Anerillas, Jennifer L Martindale, Cedric Belair, Rachel Munk, Sulochan Malla, Jinshui Fan, Yulan Piao, Xiaoling Yang, Abid Rehman, Nirad Banskota, Kotb Abdelmohsen, Myriam Gorospe, Manolis Maragkakis.

Senescence is a state of indefinite cell-cycle arrest associated with aging, cancer, and age-related diseases. Here, we find that translational deregulation, together with a corresponding maladaptive integrated stress response (ISR), is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response activating transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames (uORFs). Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. We also find that stress augments the senescence-associated secretory phenotype with sustained remodeling of inflammatory factors expression that is suppressed by non-uORF carrying ATF4 mRNA expression. Our results thus show that senescent cells possess a unique response to stress, which entails an increase in their inflammatory profile.

Keywords: ATF4; ER stress; ISR; SASP; integrated stress response; nanopore direct RNA sequencing; proteomics; ribosome sequencing; senescence; senescence-associated secretory phenotype; translation

DOI: https://doi.org/10.1016/j.molcel.2024.10.003