Cross-talk in transcription, splicing and chromatin: who makes the first call?

Alexander, Ross D.; Beggs, Jean D.

doi:10.1042/bst0381251

Cited by 44 publications

(38 citation statements)

References 59 publications

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“…This competition is important in splice site selection. 31 Targeting the spliceosome in multiple ways activates p53 The effects of Prpf8 or UBL5 suppression suggest that targeting the RNA splicing machinery can activate p53. To determine the generality of this, four additional proteins involved in different subcomplexes of the spliceosome were knocked down.…”

Section: Resultsmentioning

confidence: 99%

p53 is activated in response to disruption of the pre-mRNA splicing machinery

et al. 2012

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In this study, we show that interfering with the splicing machinery results in activation of the tumour-suppressor p53. The spliceosome was targeted by small interfering RNA-mediated knockdown of proteins associated with different small nuclear ribonucleoprotein complexes and by using the small-molecule splicing modulator TG003. These interventions cause: the accumulation of p53, an increase in p53 transcriptional activity and can result in p53-dependent G(1) cell cycle arrest. Mdm2 and MdmX are two key repressors of p53. We show that a decrease in MdmX protein level contributes to p53 activation in response to targeting the spliceosome. Interfering with the spliceosome also causes an increase in the rate of degradation of Mdm2. Alterations in splicing are linked with tumour development. There are frequently global changes in splicing in cancer. Our study suggests that p53 activation could participate in protection against potential tumour-promoting defects in the spliceosome. A number of known p53-activating agents affect the splicing machinery and this could contribute to their ability to upregulate p53. Preclinical studies indicate that tumours can be more sensitive than normal cells to small-molecule spliceosome inhibitors. Activation of p53 could influence the selective anti-tumour activity of this therapeutic approach.

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Section: Resultsmentioning

confidence: 99%

p53 is activated in response to disruption of the pre-mRNA splicing machinery

et al. 2012

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“…It is now widely accepted that maturation of nascent primary transcripts, including splicing, could occur cotranscriptionally (Kornblihtt, 2007;Manley, 2002;Neugebauer, 2002;Pandit et al, 2008;Perales and Bentley, 2009). Recently, another level in the cross-talk between transcription and splicing has been identified: histone modifications of chromatin (Alexander and Beggs, 2010;Brown et al, 2012;Hnilicová and Staněk, 2011;Luco et al, 2011). Notably, H3K79me1 was found to be enriched, together with other histone modifications, in nucleosomes positioned over exons, suggesting that H3K79 methylation has a role in splicing (Andersson et al, 2009;Dhami et al, 2010;Ernst and Kellis, 2010;Schwartz et al, 2009).…”

Section: Discussionmentioning

confidence: 98%

The tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated histone H3 lysine 79

Sabra¹,

Texier²,

Maalouf³

et al. 2013

Journal of Cell Science

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SummarySpinal muscular atrophy (SMA) is a muscular disease characterized by the death of motoneurons, and is a major genetic cause of infant mortality. Mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), are responsible for the disease. SMN belongs to the Tudor domain protein family, whose members are known to interact with methylated arginine (R) or lysine (K) residues. SMN has well-defined roles in the metabolism of small non-coding ribonucleoproteins (snRNPs) and spliceosome activity. We previously showed that SMN relocated to damaged interphase centromeres, together with the Cajal-body-associated proteins coilin and fibrillarin, during the so-called interphase centromere damage response (iCDR). Here we reveal that SMN is a chromatin-binding protein that specifically interacts with methylated histone H3K79, a gene expression-and splicing-associated histone modification. SMN relocation to damaged centromeres requires its functional Tudor domain and activity of the H3K79 methyltransferase DOT1L. In vitro pulldown assays showed that SMN interacts with H3K79me1,2 at its functional Tudor domain. Chromatin immunoprecipitation confirmed that SMN binds to H3K79me1,2-containing chromatin in iCDR-induced cells. These data reveal a novel SMN property in the detection of specific chromatin modifications, and shed new light on the involvement of a putative epigenetic dimension to the occurrence of SMA.

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“…Although further studies are required to answer this question, the disturbance of alternative splicing by SSA treatment has been found only in limited genes (35). Transcription affects splicing and vice versa, but much remains to be learned about how these processes are coupled (36)(37)(38) Tables S4 and S5), but it was below the detection levels in HeLa nuclear extracts (Supplementary Tables S3 and S4). …”

Section: Discussionmentioning

confidence: 99%

SAP155-Mediated Splicing of FUSE-Binding Protein-Interacting Repressor Serves as a Molecular Switch for c-myc Gene Expression

Matsushita

Kajiwara

Tamura

et al. 2012

Molecular Cancer Research

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The Far UpStream Element (FUSE)-binding protein-interacting repressor (FIR), a c-myc transcriptional suppressor, is alternatively spliced removing the transcriptional repression domain within exon 2 (FIRDexon2) in colorectal cancers. SAP155 is a subunit of the essential splicing factor 3b (SF3b) subcomplex in the spliceosome. This study aims to study the significance of the FIR-SAP155 interaction for the coordination of c-myc transcription, premRNA splicing, and c-Myc protein modification, as well as to interrogate FIRDexon2 for other functions relating to altered FIR pre-mRNA splicing. Knockdown of SAP155 or FIR was used to investigate their reciprocal influence on each other and on c-myc transcription, pre-mRNA splicing, and protein expression. Pull down from HeLa cell nuclear extracts revealed the association of FIR, FIRDexon2, and SF3b subunits. FIR and FIRDexon2 were coimmunoprecipitated with SAP155. FIR and FIRDexon2 adenovirus vector (Ad-FIR and Ad-FIRDexon2, respectively) were prepared to test for their influence on c-myc expression. FIR, SAP155, SAP130, and c-myc were coordinately upregulated in human colorectal cancer. These results reveal that SAP155 and FIR/FIRDexon2 form a complex and are mutually upregulating. Ad-FIRDexon2 antagonized Ad-FIR transcriptional repression of c-myc in HeLa cells. Because FIRDexon2 still carries RRM1 and RRM2 and binding activity to FUSE, it is able to displace repression competent FIR from FUSE in electrophoretic mobility shift assays, thus thwarting FIR-mediated transcriptional repression by FUSE. Thus aberrant FIRDexon2 production in turn sustained c-Myc expression. In conclusion, altered FIR and c-myc pre-mRNA splicing, in addition to c-Myc expression by augmented FIR/FIRDexon2-SAP155 complex, potentially contribute to colorectal cancer development.

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Cross-talk in transcription, splicing and chromatin: who makes the first call?

Cited by 44 publications

References 59 publications

p53 is activated in response to disruption of the pre-mRNA splicing machinery

p53 is activated in response to disruption of the pre-mRNA splicing machinery

The tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated histone H3 lysine 79

SAP155-Mediated Splicing of FUSE-Binding Protein-Interacting Repressor Serves as a Molecular Switch for c-myc Gene Expression

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