Paraquat Modulates Alternative Pre-mRNA Splicing by Modifying the Intracellular Distribution of SRPK2

Vivarelli, Silvia; Lenzken, Silvia C.; Ruepp, Marc-David; Ranzini, Francesco; Maffioletti, Andrea; Alvarez, Reinaldo; Mühlemann, Oliver; Barabino, Silvia M.L.

doi:10.1371/journal.pone.0061980

Cited by 23 publications

(35 citation statements)

References 38 publications

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“…However, retrograde signaling experiments, although informative, do not reflect the physiological role of the natural variation of mitochondrial content on gene expression regulation. Mitochondrial DNA depletion causes, among others, increased reactive oxygen species (ROS) production and perturbation of cytosolic Ca 2+ , which both signal to the cell nucleus (Chae et al 2013;Guha et al 2014), affecting processes like alternative splicing (Vivarelli et al 2013). We have analyzed the contribution of ROS to RNA Pol II transcription and ATP production, and we have seen that both processes are very sensitive to ROS (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

et al. 2015

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Noise in gene expression is a main determinant of phenotypic variability. Increasing experimental evidence suggests that genome-wide cellular constraints largely contribute to the heterogeneity observed in gene products. It is still unclear, however, which global factors affect gene expression noise and to what extent. Since eukaryotic gene expression is an energy demanding process, differences in the energy budget of each cell could determine gene expression differences. Here, we quantify the contribution of mitochondrial variability (a natural source of ATP variation) to global variability in gene expression. We find that changes in mitochondrial content can account for ∼50% of the variability observed in protein levels. This is the combined result of the effect of mitochondria dosage on transcription and translation apparatus content and activities. Moreover, we find that mitochondrial levels have a large impact on alternative splicing, thus modulating both the abundance and type of mRNAs. A simple mathematical model in which mitochondrial content simultaneously affects transcription rate and splicing site choice can explain the alternative splicing data. The results of this study show that mitochondrial content (and/or probably function) influences mRNA abundance, translation, and alternative splicing, which ultimately affects cellular phenotype.[Supplemental material is available for this article.] Cellular heterogeneity can result from noise generated during gene expression and plays an essential role in fundamental processes such as development, cell differentiation, and cancer (Raj and van Oudenaarden 2008;Eldar and Elowitz 2010;Balázsi et al. 2011). Gene expression noise may originate from stochasticity in the biochemical reactions at an individual gene (intrinsic noise) or from fluctuations in cellular components inducing a global effect (extrinsic noise) (Elowitz et al. 2002;Maheshri and O'Shea 2007). Extrinsic noise is often a dominant source of variation both in prokaryotes (Taniguchi et al. 2010) and eukaryotes (Raser and O'Shea 2004;Newman et al. 2006). Despite this, the origins of extrinsic fluctuations are mostly unknown, although random protein partitioning from cell growth and division (Rosenfeld et al. 2005;Volfson et al. 2006), upstream transcription factors (Volfson et al. 2006), or cell cycle stage (Zopf et al. 2013) have been shown to contribute to variability in protein levels. A common constraint across eukaryotic gene expression is its high energy cost (with ∼75% of the ATP cellular energy budget invested into mRNA and protein polymerization) (Forster et al. 2003;Wagner 2005;Lane and Martin 2010), where every step, from chromatin remodeling to transcription elongation, assembly of splicing factors, and translation, depends on energy (Fig. 1A). Since most of the energy required in normal cells is supplied by mitochondrial oxidative phosphorylation (Vander Heiden et al. 2009), variability in the number and/or functionality of mitochondria is a natural source of variability in ATP content...

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Section: Discussionmentioning

confidence: 99%

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

et al. 2015

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“…Cisplatin provokes the nuclear accumulation of SRPK1 and SRPK2 kinases to increase the phosphorylation of SR proteins [ 56 ]. IR and reactive oxygen species (ROS) also elicit the nuclear accumulation of SRPK2 [ 156 ]. On the other hand, UV irradiation induces a dynamic redistribution of SRSF1, SRSF9, SRSF7, U1-70K, hTra2β and NONO to areas around nucleolar fibrillar components [ 157 ].…”

Section: Dna Damage Relocalizes Splicing Factorsmentioning

confidence: 99%

“…ROS production also affects the alternative splicing of genes involved in the DDR (e.g., Ercc1 for DNA repair, Hras and Skp2 for cell-cycle control, and Apaf1 and Bin1 for apoptosis) [ 156 ]. Finally, bleomycin reduces the expression of SF3B1 and increases the production of a splice variant of FIR (aka PUF60, a U2AF2-related protein) that is deficient in its ability to confer transcriptional repression of c-myc [ 240 ].…”

Section: Dna Damage Modulates the Alternative Splicing Of Genes Inmentioning

confidence: 99%

The RNA Splicing Response to DNA Damage

2015

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The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring the formation of RNA/DNA duplexes, splicing factors are also recruited to, or removed from, sites of DNA damage. The first steps of the DDR promote the post-translational modification of splicing factors to affect their localization and activity, while more downstream DDR events alter their expression. Although descriptions of molecular mechanisms remain limited, an emerging trend is that DNA damage disrupts the coupling of constitutive and alternative splicing with the transcription of genes involved in DNA repair, cell-cycle control and apoptosis. A better understanding of how changes in splice site selection are integrated into the DDR may provide new avenues to combat cancer and delay aging.

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“…Here, their reimport into the nucleus requires phosphorylation by SRPK1 and SRPK2, two SR protein kinases that are predominantly localized in the cytoplasm. It was recently shown that genotoxic stress can induce the phosphorylation and the relocalization of these kinases to the nucleus where they in turn hyperphosphorylate SR proteins leading to changes in pre-mRNA splicing [22, 23]. Moreover, chronic replication-dependent DNA damage was shown to induce the hyperphosphorylation of ASF/SF2 (SRSF1) [24].…”

Section: How Ddr Can Affect Alternative Pre-mrna Splicing (As)mentioning

confidence: 99%

“…Moreover, splicing factors' depletion may slow down intron removal favoring the formation of DNA/RNA hybrid thereby leading to the collapse of replication forks and to the generation of DSBs [108, 112, 113]. Finally, the activation of the DDR can promote the posttranslational modification of splicing factors altering their intracellular localization and/or their activity [22, 23, 41, 46, 134]. Although some aspects of the relationship between DDR and mRNA processing have been clarified, certain observations are still to be explained.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

RNA Splicing: A New Player in the DNA Damage Response

Lenzken

Loffreda

Barabino

2013

International Journal of Cell Biology

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It is widely accepted that tumorigenesis is a multistep process characterized by the sequential accumulation of genetic alterations. However, the molecular basis of genomic instability in cancer is still partially understood. The observation that hereditary cancers are often characterized by mutations in DNA repair and checkpoint genes suggests that accumulation of DNA damage is a major contributor to the oncogenic transformation. It is therefore of great interest to identify all the cellular pathways that contribute to the response to DNA damage. Recently, RNA processing has emerged as a novel pathway that may contribute to the maintenance of genome stability. In this review, we illustrate several different mechanisms through which pre-mRNA splicing and genomic stability can influence each other. We specifically focus on the role of splicing factors in the DNA damage response and describe how, in turn, activation of the DDR can influence the activity of splicing factors.

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Paraquat Modulates Alternative Pre-mRNA Splicing by Modifying the Intracellular Distribution of SRPK2

Cited by 23 publications

References 38 publications

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

The RNA Splicing Response to DNA Damage

RNA Splicing: A New Player in the DNA Damage Response

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