SF3B1 is a stress-sensitive splicing factor that regulates both HSF1 concentration and activity

Guisbert, Karen S. Kim; Guisbert, Eric

doi:10.1371/journal.pone.0176382

Cited by 19 publications

(19 citation statements)

References 38 publications

(42 reference statements)

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“…Our observations raise the possibility that splicing disruptions leading to readthrough transcription represent a common molecular link underlying DoG transcription. In support of this, SF3B1 is a stresssensitive splicing factor that responds to heat shock (Kim Guisbert and Guisbert, 2017). In addition, we note that these cellular stresses and viral infections also led to a broad repression of transcription and gene expression, as observed here upon splicing disruption.…”

Section: Pladb-induced Transcriptional Alterations Resemble Other Strsupporting

confidence: 73%

SF3B1-targeted Splicing Inhibition Triggers Global Alterations in Transcriptional Dynamics and R-Loop Metabolism

Castillo-Guzman

Hartono

Sanz

et al. 2020

Preprint

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Efficient co-transcriptional splicing is thought to suppress the formation of genome-destabilizing R-loops upon interaction between nascent RNA and the DNA template. Inhibition of the SF3B splicing complex using Pladienolide B (PladB) in human K562 cells caused widespread intron retention and nearly 2,000 instances of R-loops gains. However, only minimal overlap existed between these events, arguing that unspliced introns do not cause excessive R-loops. R-loop gains were instead driven by readthrough transcription resulting from loss of transcription termination over a subset of stress-response genes, defining a new class of aberrant "downstream of genes" (DoG) R-loops. Such DoG R-loops were temporally and spatially uncoupled from loci experiencing DNA damage. Unexpectedly, the predominant response to splicing inhibition was a global R-loop loss resulting from accumulation of promoter-proximal paused RNA polymerases and defective elongation. Thus, SF3B1-targeted splicing inhibition triggered profound alterations in transcriptional dynamics, leading to unexpected disruptions in the global R-loop landscape. HIGHLIGHTS • Intron retention caused by SF3B1 inhibition does not lead to excessive R-loops • A subset of genes shows readthrough transcription and accompanying R-loop gains • SF3B1 inhibition causes broad reduction in nascent transcription and R-loop loss • R-loop gains and DNA damage are temporally and spatially uncoupled RNAPII RNA +PladB PAS zZz Promoter pausing Elongation R-loops downstream of gene PAS zZz R-loops Txn read through DoG R-loops Promoter pausing Elongation No R-loop PAS zZz

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Section: Pladb-induced Transcriptional Alterations Resemble Other Strsupporting

confidence: 73%

SF3B1-targeted Splicing Inhibition Triggers Global Alterations in Transcriptional Dynamics and R-Loop Metabolism

Castillo-Guzman

Hartono

Sanz

et al. 2020

Preprint

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“…At present, studies on the important role of SF3B1 have mainly focused on humans and animals, while its role in plants has not been reported. Kim Guisbert et al [64] revealed that SF3B1 regulates the activity of the heat shock transcription factor (HSF1) via mRNA splicing to enhance stress-sensitive abilities. In this study, eight phosphosites in the SF3B1 were up-expressed in Cd + N treated plants, which indicated that SF3B1 may modulate poplar plants' resistant to Cd stress by mRNA splicing at the transcriptome.…”

Section: Exogenous Nitrogen Promoted Protein Phosphorylation To Enhanmentioning

confidence: 99%

Changes in Proteome and Protein Phosphorylation Reveal the Protective Roles of Exogenous Nitrogen in Alleviating Cadmium Toxicity in Poplar Plants

Huang

Tian

et al. 2019

IJMS

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Phytoremediation soil polluted by cadmium has drawn worldwide attention. However, how to improve the efficiency of plant remediation of cadmium contaminated soil remains unknown. Previous studies showed that nitrogen (N) significantly enhances cadmium uptake and accumulation in poplar plants. In order to explore the important role of nitrogen in plants’ responses to cadmium stress, this study investigates the poplar proteome and phosphoproteome difference between Cd stress and Cd + N treatment. In total, 6573 proteins were identified, and 5838 of them were quantified. With a fold-change threshold of > 1.3, and a p-value < 0.05, 375 and 108 proteins were up- and down-regulated by Cd stress when compared to the control, respectively. Compared to the Cd stress group, 42 and 89 proteins were up- and down-regulated by Cd + N treatment, respectively. Moreover, 522 and 127 proteins were up- and down-regulated by Cd + N treatment compared to the CK group. In addition, 1471 phosphosites in 721 proteins were identified. Based on a fold-change threshold of > 1.2, and a p-value < 0.05, the Cd stress up-regulated eight proteins containing eight phosphosites, and down-regulated 58 proteins containing 69 phosphosites, whereas N + Cd treatment up-regulated 86 proteins containing 95 phosphosites, and down-regulated 17 proteins containing 17 phosphosites, when compared to Cd stress alone. N + Cd treatment up-regulated 60 proteins containing 74 phosphosites and down-regulated 37 proteins containing 42 phosphosites, when compared to the control. Several putative responses to stress proteins, as well as transcriptional and translational regulation factors, were up-regulated by the addition of exogenous nitrogen following Cd stress. Especially, heat shock protein 70 (HSP70), 14-3-3 protein, peroxidase (POD), zinc finger protein (ZFP), ABC transporter protein, eukaryotic translation initiation factor (elF) and splicing factor 3 B subunit 1-like (SF3BI) were up-regulated by Cd + N treatment at both the proteome and the phosphoproteome levels. Combing the proteomic data and phosphoproteomics data, the mechanism by which exogenous nitrogen can alleviate cadmium toxicity in poplar plants was explained at the molecular level. The results of this study will establish the solid molecular foundation of the phytoremediation method to improve cadmium-contaminated soil.

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“…As such, the spliceosome has emerged as an attractive target for anticancer treatment [16]. SF3b1 is a principal player in the spliceosome and a target of inhibitor compounds [17,18]. Several spliceosome modulators have already been identified [19].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SF3b1 by pladienolide B evokes cycle arrest, apoptosis induction and p73 splicing in human cervical carcinoma cells

Zhang

Chen

Yan

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Pladienolide B is a potent cancer cell growth inhibitor that targets the SF3b1 subunit of the spliceosome. There is considerable interest in the compound as a tool to study SF3b1 function in cancer. However, so far little information is available on the molecular mechanism of SF3b1 eliciting apoptosis in cancer cells. Here, we investigated the molecular mechanism of SF3b1 eliciting apoptosis in human cervical carcinoma cells. We demonstrated that inhibition of SF3b1 by pladienolide B inhibited proliferation of HeLa cells at low nanomolar concentrations in a dose-and time-dependent manner. It also induced G2/M phase arrest and significant rise of apoptotic cells. Moreover, it is indicated that inhibition of SF3b1 by pladienolide B induced Tap73/DNp73 expression and consequently down-regulated Bax/Bcl-2 ratio, cytochrome c release and caspase-3 expression. Thus, our results showed that SF3b1 plays a pivotal role in cycle arrest, apoptosis induction, and p73 splicing in human cervical carcinoma cells, suggesting that SF3b1 could be used as a potential candidate for cervical cancer therapy.

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SF3B1 is a stress-sensitive splicing factor that regulates both HSF1 concentration and activity

Cited by 19 publications

References 38 publications

SF3B1-targeted Splicing Inhibition Triggers Global Alterations in Transcriptional Dynamics and R-Loop Metabolism

SF3B1-targeted Splicing Inhibition Triggers Global Alterations in Transcriptional Dynamics and R-Loop Metabolism

Changes in Proteome and Protein Phosphorylation Reveal the Protective Roles of Exogenous Nitrogen in Alleviating Cadmium Toxicity in Poplar Plants

Inhibition of SF3b1 by pladienolide B evokes cycle arrest, apoptosis induction and p73 splicing in human cervical carcinoma cells

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