Sudemycin E influences alternative splicing and changes chromatin modifications

Convertini, Paolo; Shen, Minhong; Potter, Philip M.; Palacios, Gustavo; Lagisetti, Chandraiah; Grange, Pierre de la; Horbinski, Craig; Fondufe‐Mittendorf, Yvonne; Webb, Thomas R.; Stamm, Stefan

doi:10.1093/nar/gku151

Cited by 61 publications

(74 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[149][150][151] Another closely related molecule, sudemycin E, also has been shown to alter splicing. 152 Cells treated with sudemycin E were arrested in G2 and showed increased cell death. It has been suggested that this is due to changes in alternative splicing as well as changes in chromatin condensation.…”

Section: Modulating Alternative Splicing As a Novel Therapeutic Approachmentioning

confidence: 99%

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

Shilo

Siegfried

Karni

2014

Molecular & Cellular Oncology

View full text Add to dashboard Cite

In past decades, cancer research has focused on genetic alterations that are detected in malignant tissues and contribute to the initiation and progression of cancer. These changes include mutations, copy number variations, and translocations. However, it is becoming increasingly clear that epigenetic changes, including alternative splicing, play a major role in cancer development and progression. There are relatively few studies on the contribution of alternative splicing and the splicing factors that regulate this process to cancer development and progression. Recently, multiple studies have revealed altered splicing patterns in cancers and several splicing factors were found to contribute to tumor development. Studies using high-throughput genomic analysis have identified mutations in components of the core splicing machinery and in splicing factors in several cancers. In this review, we will highlight new findings on the role of alternative splicing and its regulators in cancer initiation and progression, in addition to novel approaches to correct oncogenic splicing.

show abstract

Section: Modulating Alternative Splicing As a Novel Therapeutic Approachmentioning

confidence: 99%

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

Shilo

Siegfried

Karni

2014

Molecular & Cellular Oncology

View full text Add to dashboard Cite

show abstract

“…These silencing marks recruit the heterochromatin protein HP1 and create roadblocks for RNAPII elongation, which in turn upregulates or downregulates alternative exon inclusion, depending on the nature of the alternative splicing event, through kinetic coupling. Experiments supporting this model are described in References 189 and 220. that inhibit the activity of the U2 snRNP component SF3B1 results in loss of the H3K36me3 mark (196). Depletion of SF3B3, a core spliceosome component, decreases Kmt3a recruitment to chromatin and reduces H3K36me3 levels (197).…”

Section: Influence Of Splicing On Chromatin Structurementioning

confidence: 99%

Regulation of Alternative Splicing Through Coupling with Transcription and Chromatin Structure

Naftelberg

Schor²,

Ast³

et al. 2015

Annu. Rev. Biochem.

391

354

View full text Add to dashboard Cite

Alternative precursor messenger RNA (pre-mRNA) splicing plays a pivotal role in the flow of genetic information from DNA to proteins by expanding the coding capacity of genomes. Regulation of alternative splicing is as important as regulation of transcription to determine cell- and tissue-specific features, normal cell functioning, and responses of eukaryotic cells to external cues. Its importance is confirmed by the evolutionary conservation and diversification of alternative splicing and the fact that its deregulation causes hereditary disease and cancer. This review discusses the multiple layers of cotranscriptional regulation of alternative splicing in which chromatin structure, DNA methylation, histone marks, and nucleosome positioning play a fundamental role in providing a dynamic scaffold for interactions between the splicing and transcription machineries. We focus on evidence for how the kinetics of RNA polymerase II (RNAPII) elongation and the recruitment of splicing factors and adaptor proteins to chromatin components act in coordination to regulate alternative splicing.

show abstract

“…In cells, treatment with SF3B1 inhibitors leads to changes in alternative splicing of genes involved in apoptosis and the cell cycle, among others (Kaida et al 2007;Kotake et al 2007;Lagisetti et al 2009;Corrionero et al 2011;Hasegawa et al 2011;Convertini et al 2014;Effenberger et al 2014). Microarray analysis of 2000 splicing events from nearly 500 genes suggested that SSA affects alternative splicing of introns with weak branch points (Corrionero et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages

Effenberger

Urabe

Prichard

et al. 2016

RNA

102

View full text Add to dashboard Cite

The protein SF3B1 is a core component of the spliceosome, the large ribonucleoprotein complex responsible for pre-mRNA splicing. Interest in SF3B1 intensified when tumor exome sequencing revealed frequent specific SF3B1 mutations in a variety of neoplasia and when SF3B1 was identified as the target of three different cancer cell growth inhibitors. A better mechanistic understanding of SF3B1's role in splicing is required to capitalize on these discoveries. Using the inhibitor compounds, we probed SF3B1 function in the spliceosome in an in vitro splicing system. Formerly, the inhibitors were shown to block early steps of spliceosome assembly, consistent with a previously determined role of SF3B1 in intron recognition. We now report that SF3B1 inhibitors also interfere with later events in the spliceosome cycle, including exon ligation. These observations are consistent with a requirement for SF3B1 throughout the splicing process. Additional experiments aimed at understanding how three structurally distinct molecules produce nearly identical effects on splicing revealed that inactive analogs of each compound interchangeably compete with the active inhibitors to restore splicing. The competition indicates that all three types of compounds interact with the same site on SF3B1 and likely interfere with its function by the same mechanism, supporting a shared pharmacophore model. It also suggests that SF3B1 inhibition does not result from binding alone, but is consistent with a model in which the compounds affect a conformational change in the protein. Together, our studies reveal new mechanistic insight into SF3B1 as a principal player in the spliceosome and as a target of inhibitor compounds.

show abstract

Sudemycin E influences alternative splicing and changes chromatin modifications

Cited by 61 publications

References 40 publications

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

Regulation of Alternative Splicing Through Coupling with Transcription and Chromatin Structure

Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages

Contact Info

Product

Resources

About