Dynamics and functional roles of splicing factor autoregulation

Ding, Fangyuan; Su, Christina; Edmonds, KeHuan Kuo; Liang, Guohao; Elowitz, Michael B.

doi:10.1016/j.celrep.2022.110985

Cited by 15 publications

(11 citation statements)

References 79 publications

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“…Our investigation further revealed that large-scale splicing alterations could be attributed not only to SF3B1 inactivation but also to a compensatory response by the cell, involving increased expression of approximately 50 spliceosomal proteins, including SF3B1 itself. This compensatory mechanism, previously observed in splicing factors of the hnRNP or SR families, involves negative autoregulatory pathways 45–47 . These splicing factors are known to participate in the splicing of their own pre-mRNA generating unproductive isoforms with premature termination codons, which are then degraded by the NMD pathway 24 .…”

Section: Discussionmentioning

confidence: 65%

Unlocking DNA Damage Sensitivity of Cancer Cells: The Potential of Splicing Inhibitors

Anufrieva,

Lukina,

Ivanova

et al. 2023

Preprint

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Despite the growing interest in pre-mRNA alternative splicing (AS) as a therapeutic anticancer target, the potential of splicing inhibitors in treating solid tumors remains largely unexplored. We conducted a meta-analysis of transcriptome data from six different tumor types and revealed that splicing inhibitors induced similar patterns of AS, resulting in widespread exon-skipping and intron retention events that often lead to nonsense-mediated decay of the transcripts. Interestingly, in many cases exon skipping is induced by a compensatory cellular response to splicing inhibitor treatment. It involves an upregulation of multiple splicing factors and incomplete recognition of branch points by U2 snRNP. These post transcriptional changes downregulate one-third of essential DNA repair genes, thereby creating a therapeutic vulnerability that can be exploited for cancer treatment. To harness this vulnerability, we proposed a new approach to cancer treatment consisting of sequential addition of a splicing inhibitors followed by a DNA-damaging agent. Ourin vitroandin vivoexperiments demonstrated that this strategy exhibits promising therapeutic potential for a wide range of tumors.

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Section: Discussionmentioning

confidence: 65%

Unlocking DNA Damage Sensitivity of Cancer Cells: The Potential of Splicing Inhibitors

Anufrieva,

Lukina,

Ivanova

et al. 2023

Preprint

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“…Gene ontology (GO) enrichment analysis of the genes with DTSs showed enrichment of pathways related to RNA regulation, such as mRNA binding, translational initiation and RNA catabolic process (Figure 3C). This suggests potential autoregulation of these genes, which is frequently observed for RNA-binding proteins, particularly splicing factors (Ding et al, 2022;Dredge et al, 2005;Guo et al, 2015). Several immunological pathways were also implicated, indicating that DTS may contribute to dysregulated immunological activity in tumor cells.…”

Section: Dysregulation Of Transcript Structure and Rna Editing In Tum...mentioning

confidence: 89%

An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing

Zhang

Chan

et al. 2023

Preprint

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Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. In recent years, short-read single-cell RNA sequencing (scRNA-seq) has been instrumental in deciphering tumor cell heterogeneities. However, these studies only enable gene-level expression quantification but neglect alterations in transcript structures, which arise from alternative end processing or splicing, and are frequently observed in cancer. In this study, we integrated short- and long-read scRNA-seq of CRC patient samples to build the first isoform-resolution CRC transcriptomic atlas. We identified 394 dysregulated transcript structures in tumor epithelial cells, including 299 resulting from various combinations of multiple splicing events. Secondly, we characterized genes and isoforms associated with epithelial lineages and subpopulations that exhibit distinct prognoses. Finally, we built an algorithm that integrated novel peptides derived from predicted ORFs of recurrent tumor-specific transcripts with mass spectrometry data and identified a panel of recurring neoepitopes that may aid the development of neoantigen-based cancer vaccines.

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“…Since Myc expression was shown to be reduced by elevated levels of IFN-I ( 135 – 137 ), the observed reduction in SRSF1 mRNA expression could potentially result from depleted Myc levels. Furthermore, SRSF1 was shown to maintain homeostasis through an autoregulatory feedback loop ( 138 , 139 ). Since deregulation of SRSF1 was shown to be involved in tumorigenesis ( 133 ) ( 140 , 141 ), tight regulation of SRSF1 expression is important for normal cell physiology.…”

Section: Discussionmentioning

confidence: 99%

“…The most abundant SRSF1 transcript isoform is the productively translated and intron-containing isoform 1 ( 139 ). Upon elevated levels of SRSF1, the degradation of SRSF1 transcripts via RNA surveillance pathways, such as nonsense-mediated decay (NMD), is induced through the removal of introns ( 77 , 138 , 142 ). Thus, upon strongly elevated levels of freshly synthesized SRSF1 mRNA, the negative feedback loop could induce a higher frequency in intron removal, possibly resulting in the observed strong downregulation in SRSF1 mRNA transcripts at later time points.…”

Section: Discussionmentioning

confidence: 99%

“…Certain accessory proteins like Nef might, in addition to counteracting restriction factors such as tetherin ( 14 , 155 ), also modulate signal transduction, autoregulation mechanisms, antigen presentation, or the expression of cell surface receptors [reviewed in ( 156 – 158 )]. Since an autoregulatory feedback loop was shown to maintain homeostatic levels of SRSF1 ( 77 , 138 , 142 ), interaction of accessory proteins with this autoregulation might potentially explain the observed recovery in the mRNA expression kinetic ( Figure 4E ). Experimentally, it is challenging to distinguish between HIV-1-infected cells producing IFNα and bystander cells, which induce gene expression of HIV restriction factors prior to the infection, thus inhibiting pre-integration steps.…”

Section: Discussionmentioning

confidence: 99%

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SRSF1 acts as an IFN-I-regulated cellular dependency factor decisively affecting HIV-1 post-integration steps

Sertznig¹,

Roesmann

Wilhelm

et al. 2022

Front. Immunol.

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Efficient HIV-1 replication depends on balanced levels of host cell components including cellular splicing factors as the family of serine/arginine-rich splicing factors (SRSF, 1–10). Type I interferons (IFN-I) play a crucial role in the innate immunity against HIV-1 by inducing the expression of IFN-stimulated genes (ISGs) including potent host restriction factors. The less well known IFN-repressed genes (IRepGs) might additionally affect viral replication by downregulating host dependency factors that are essential for the viral life cycle; however, so far, the knowledge about IRepGs involved in HIV-1 infection is very limited. In this work, we could demonstrate that HIV-1 infection and the associated ISG induction correlated with low SRSF1 levels in intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) during acute and chronic HIV-1 infection. In HIV-1-susceptible cell lines as well as primary monocyte-derived macrophages (MDMs), expression levels of SRSF1 were transiently repressed upon treatment with specific IFNα subtypes in vitro. Mechanically, 4sU labeling of newly transcribed mRNAs revealed that IFN-mediated SRSF1 repression is regulated on early RNA level. SRSF1 knockdown led to an increase in total viral RNA levels, but the relative proportion of the HIV-1 viral infectivity factor (Vif) coding transcripts, which is essential to counteract APOBEC3G-mediated host restriction, was significantly reduced. In the presence of high APOBEC3G levels, however, increased LTR activity upon SRSF1 knockdown facilitated the overall replication, despite decreased vif mRNA levels. In contrast, SRSF1 overexpression significantly impaired HIV-1 post-integration steps including LTR transcription, alternative splice site usage, and virus particle production. Since balanced SRSF1 levels are crucial for efficient viral replication, our data highlight the so far undescribed role of SRSF1 acting as an IFN-modulated cellular dependency factor decisively regulating HIV-1 post-integration steps.

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Dynamics and functional roles of splicing factor autoregulation

Cited by 15 publications

References 79 publications

Unlocking DNA Damage Sensitivity of Cancer Cells: The Potential of Splicing Inhibitors

Unlocking DNA Damage Sensitivity of Cancer Cells: The Potential of Splicing Inhibitors

An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing

SRSF1 acts as an IFN-I-regulated cellular dependency factor decisively affecting HIV-1 post-integration steps

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