The emerging role of pre-messenger RNA splicing in stress responses: Sending alternative messages and silent messengers

Dutertre, Martin; Sanchez, Gabriel; Barbier, Jérôme; Corcos, Laurent; Auboeuf, Didier

doi:10.4161/rna.8.5.16016

Cited by 98 publications

(97 citation statements)

References 65 publications

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“…Thus, cell responses to DNA damage may involve the coordinated regulation of both nuclear and cytoplasmic sets of transcripts by HuR. Large-scale regulation of alternative polyadenylation and splicing are increasingly involved in cellular processes, including proliferation and genotoxic responses, respectively [1][2][3][4][5][6][7][8]16,[19][20][21] . In this context, our data provide several advances.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to splicing regulations mediated by the EWS protein and targeting several key effectors of the DNA damage response 22,57 , ALE regulation mediated by HuR and targeting several genes involved in DNA damage response and cell cycle (for example, CENPN, KIF1B and MBD1) appears as a novel pathway of regulation of pre-mRNA maturation mediating genotoxic stress responses. Other such pathways likely remain to be identified, because other splicing factors are affected by DNA-damaging agents 16 . Characterization of these pathways should help understand cell responses to different classes of genotoxic agents.…”

Section: Discussionmentioning

confidence: 99%

“…One biological setting where alternative transcripts are emerging as important new players is the response of cells to DNA-damaging agents 16 . These responses involve a partial repression of gene expression, accompanied by the selective upregulation of genes involved in DNA repair, cell cycle arrest and eventually cell death, which is coordinated in a large part by the p53 transcription factor.…”

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confidence: 99%

“…Likewise, UV irradiation partially inhibits cleavage/polyadenylation 17 , but p53 transcripts escape such repression 18 . Several genes involved in the DNA damage response, such as MDM2 that encodes the main repressor of p53, are regulated at the splicing level in response to genotoxic agents 16 . Recently, UV irradiation and the topoisomerase (TOP) I inhibitor, camptothecin (CPT), were shown to increase the inclusion of many cassette exons through an inhibition of transcription elongation, which gives more time for the cotranscriptional recognition and inclusion of alternative exons [19][20][21] .…”

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A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

et al. 2014

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Alternative 3 0 -terminal exons, which use intronic polyadenylation sites, are generally less conserved and expressed at lower levels than the last exon of genes. Here we discover a class of human genes, in which the last exon appeared recently during evolution, and the major gene product uses an alternative 3 0 -terminal exon corresponding to the ancestral last exon of the gene. This novel class of alternative 3 0 -terminal exons are downregulated on a large scale by doxorubicin, a cytostatic drug targeting topoisomerase II, and play a role in cell cycle regulation, including centromere-kinetochore assembly. The RNA-binding protein HuR/ ELAVL1 is a major regulator of this specific set of alternative 3 0 -terminal exons. HuR binding to the alternative 3 0 -terminal exon in the pre-messenger RNA promotes its splicing, and is reduced by topoisomerase inhibitors. These findings provide new insights into the evolution, function and molecular regulation of alternative 3 0 -terminal exons.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

et al. 2014

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“…Indeed, DNA damage and oxidative stress are potent activators of p53 signaling pathway, and the generation of p53ψ by the same stimuli may be a mechanism designed to balance p53 FL activity. Genotoxic damage has been found to trigger alternative splicing by affecting the expression or posttranslational modification of splicing factors in a way that alters their intracellular localization (14). It is therefore conceivable that p53ψ could counteract the apoptotic and cell cycle inhibitory functions of p53 FL and contribute to tissue remodeling after DNA damage.…”

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Discovery of a p53 variant that controls metastasis

Gorrini¹

2014

Proc. Natl. Acad. Sci. U.S.A.

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The tumor suppressor p53 encoded by the tumor protein 53 (TP53) gene has been extensively studied since its discovery in 1979 (1, 2). The last four decades have seen the publication of an enormous number of reports on the role of p53 in suppressing cancer formation. These studies have demonstrated that TP53 mutations are the most common genetic alterations in human tumors (3).In PNAS, an article by Senturk et al. in the laboratory of R. Sordella describes the discovery of a new p53 isoform, named p53ψ, that may contribute to, rather than prevent, tumorigenesis (4). The new p53 isoform described by Senturk et al. derives from the use of an alternative 3′ splice acceptor site within TP53 intron 6. p53ψ encodes a protein of 27 kDa that lacks the critical residues necessary for p53 oligomerization, DNA binding, and nuclear localization. As a result, p53ψ does not have transcriptional activity, does not form oligomers, and is localized principally in the cytoplasm.Before the report of Senturk et al., 12 distinct p53 isoforms were known to exist in humans (5). Alternative splicing of TP53 intron 9 and use of the alternative promoter in intron 4 generates p53FL, p53β, p53γ, Δ133p53, Δ133p53β, and Δ133p53γ. Similarly, Δ40p53, Δ40p53β, and Δ40p53γ originate from the alternative splicing of TP53 intron 9 and the initiation of translation from a promoter in intron 2. Examination of mRNA levels of p53 variants has revealed that their generation is tissue specific, suggesting that internal promoter use and alternative splicing of TP53 are differentially regulated. Moreover, protein levels of p53 variants can be affected by external stimuli such as DNA damage induced by UV or ionizing radiation or changes in pH or oxygen concentration. With respect to function, p53 isoforms differ in their subcellular localization patterns and biological activities. Some p53 variants have been shown to interfere with the activity of p53 full length (FL) in vitro (6). In vivo, abnormal expression of p53 isoforms has been associated with disruption of the p53 FL response and, consequently, with accelerated aging, shorter life span, and promotion of tumor formation (7,8).The discovery of p53ψ raises the number of known p53 isoforms to 13. As is true for other p53 isoforms, this variant differs from p53 FL in its subcellular localization and putative function. However, unlike p53 isoforms that act as dominant-negative inhibitors of p53 FL activity, p53ψ does not interfere with p53 FL's mode of action. In fact, the authors show that the down-regulation of p53 FL's transcriptional targets in p53ψ-expressing cells is due solely to the generation of p53ψ transcripts at the expense of p53 FL mRNA.Senturk et al. initially discovered p53ψ as a variant expressed in a specific cell subset isolated from the lungs of mice that had been treated with naphthalene, which rapidly induces injury and necrosis in lung tissue. This cell subset was characterized by high expression of the glycoprotein CD44 and low expression of the heat stable antigen CD24 (CD44 hi CD...

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Oleaginous Yeast Biology Elucidated With Comparative Transcriptomics

Weintraub,

Li,

Nakagawa

et al. 2024

Biotech & Bioengineering

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Extremophilic yeasts have favorable metabolic and tolerance traits for biomanufacturing‐ like lipid biosynthesis, flavinogenesis, and halotolerance – yet the connection between these favorable phenotypes and strain genotype is not well understood. To this end, this study compares the phenotypes and gene expression patterns of biotechnologically relevant yeasts Yarrowia lipolytica, Debaryomyces hansenii, and Debaryomyces subglobosus grown under nitrogen starvation, iron starvation, and salt stress. To analyze the large data set across species and conditions, two approaches were used: a “network‐first” approach where a generalized metabolic network serves as a scaffold for mapping genes and a “cluster‐first” approach where unsupervised machine learning co‐expression analysis clusters genes. Both approaches provide insight into strain behavior. The network‐first approach corroborates that Yarrowia upregulates lipid biosynthesis during nitrogen starvation and provides new evidence that riboflavin overproduction in Debaryomyces yeasts is overflow metabolism that is routed to flavin cofactor production under salt stress. The cluster‐first approach does not rely on annotation; therefore, the coexpression analysis can identify known and novel genes involved in stress responses, mainly transcription factors and transporters. Therefore, this work links the genotype to the phenotype of biotechnologically relevant yeasts and demonstrates the utility of complementary computational approaches to gain insight from transcriptomics data across species and conditions.

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The emerging role of pre-messenger RNA splicing in stress responses: Sending alternative messages and silent messengers

Cited by 98 publications

References 65 publications

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

Discovery of a p53 variant that controls metastasis

Oleaginous Yeast Biology Elucidated With Comparative Transcriptomics

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