Tumor suppressor RBM5 directly interacts with the DExD/H‐box protein DHX15 and stimulates its helicase activity

Niu, Zhaoyang; Jin, Wei; Zhang, Libo; Li, Xialu

doi:10.1016/j.febslet.2012.02.052

Cited by 58 publications

(67 citation statements)

References 25 publications

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“…However, while both proteins have the capacities to compete U2AF65 binding, overexpression of PTB had only marginal effect on AID exon 4 skipping (data not shown). These results argue that RBM5 and PTB function through distinct molecular mechanisms in splicing regulation, consistent with our recent findings that RBM5, but not PTB, specifically interacts with and stimulates the helicase activity of DHX15, a component of U2 snRNP [18].…”

Section: Discussionsupporting

confidence: 92%

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RBM5 promotes exon 4 skipping of AID pre‐mRNA by competing with the binding of U2AF65 to the polypyrimidine tract

Jin

Niu

et al. 2012

FEBS Letters

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Edited by Ulrike KutayKeywords: AID Alternative splicing RBM5 U2AF a b s t r a c t Alternative splicing is involved in functional regulation of the mutagenic enzyme activationinduced cytidine deaminase (AID). However, the molecular basis for AID splicing regulation remains undefined. Using a mini-gene-based screen in HeLa cells, we found that overexpression of RNA binding motif protein 5 (RBM5, or LUCA-15/H37) significantly promoted AID exon 4 skipping by suppressing the splicing of intron 3. The inhibitive effect of RBM5 on intron 3 splicing required a weak 3 0 -splice site (ss). Indicative of the underlying mechanism, RBM5 interfered with the binding of U2AF65 to the polypyrimidine tract at the 3 0 -ss in vitro. Our findings thus not only shed lights on the regulatory mechanism of AID exon 4 skipping, but also provide new insights into how RBM5 functions in splicing regulation.

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Section: Discussionsupporting

confidence: 92%

“…Cells were grown in the presence of 0.05 mM isopropyl b-D-1-thiogalactopyranoside (IPTG) for 24 h at 10°C. Recombinant proteins were purified as described [18].…”

Section: Purification Of Recombinant Protein From Escherichia Colimentioning

confidence: 99%

RBM5 promotes exon 4 skipping of AID pre‐mRNA by competing with the binding of U2AF65 to the polypyrimidine tract

Jin

Niu

et al. 2012

FEBS Letters

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“…Interestingly, the region outside of the DNA binding domain is similar to the synaptic vesicle protein Eps15 (E value = 6e–10, blastp), which suggests that this gene could also be associated with synaptic vesicles. Dhx15 is another highly connected gene within this module, and it is a known RNA helicase and part of the spliceosome complex (Fouraux et al, 2002; Niu et al, 2012), which is consistent with the GO analysis demonstrating enrichment of genes involved in RNA processing. Another hub gene within this module, Rnf111 , is an E3 ubiquitin ligase (Koinuma et al, 2003), which is consistent with enrichment of genes associated with ubiquitination.…”

Section: Resultssupporting

confidence: 86%

Molecular alterations in areas generating fast ripples in an animal model of temporal lobe epilepsy

Winden

Bragin

Engel

et al. 2015

Neurobiology of Disease

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The molecular basis of epileptogenesis is poorly characterized. Studies in humans and animal models have identified an electrophysiological signature that precedes the onset of epilepsy, which has been termed fast ripples (FRs) based on its frequency. Multiple lines of evidence implicate regions generating FRs in epileptogenesis, and FRs appear to demarcate the seizure onset zone, suggesting a role in ictogenesis as well. We performed gene expression analysis comparing areas of the dentate gyrus that generate FRs to those that do not generate FRs in a well-characterized rat model of epilepsy. We identified a small cohort of genes that are differentially expressed in FR versus non-FR brain tissue and used quantitative PCR to validate some of those that modulate neuronal excitability. Gene expression network analysis demonstrated conservation of gene co-expression between non-FR and FR samples, but examination of gene connectivity revealed changes that were most pronounced in the cm-40 module, which contains several genes associated with synaptic function and the differentially expressed genes Kcna4, Kcnv1, and Npy1r that are down-regulated in FRs. We then demonstrate that the genes within the cm-40 module are regulated by seizure activity and enriched for the targets of the RNA binding protein Elavl4. Our data suggest that seizure activity induces co-expression of genes associated with synaptic transmission and that this pattern is attenuated in areas displaying FRs, implicating the failure of this mechanism in the generation of FRs.

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“…In mammals, RBM5 can interact with the U2AF large subunit [30,32], the spliceosomal SmN/B/B’ proteins [30,33] and the DExD/H-box protein DHX15 [66]. How these interactions contribute to the tumor suppressor function of RBM5 is unclear.…”

Section: Discussionmentioning

confidence: 99%

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

Zhou

Gao

et al. 2018

RNA Biology

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A key step in pre-mRNA splicing is the recognition of 3ʹ splicing sites by the U2AF large and small subunits, a process regulated by numerous trans-acting splicing factors. How these trans-acting factors interact with U2AF in vivo is unclear. From a screen for suppressors of the temperature-sensitive (ts) lethality of the C. elegans U2AF large subunit gene uaf-1(n4588) mutants, we identified mutations in the RNA binding motif gene rbm-5, a homolog of the tumor suppressor gene RBM5. rbm-5 mutations can suppress uaf-1(n4588) ts-lethality by loss of function and neuronal expression of rbm-5 was sufficient to rescue the suppression. Transcriptome analyses indicate that uaf-1(n4588) affected the expression of numerous genes and rbm-5 mutations can partially reverse the abnormal gene expression to levels similar to that of wild type. Though rbm-5 mutations did not obviously affect alternative splicing per se, they can suppress or enhance, in a gene-specific manner, the altered splicing of genes in uaf-1(n4588) mutants. Specifically, the recognition of a weak 3ʹ splice site was more susceptible to the effect of rbm-5. Our findings provide novel in vivo evidence that RBM-5 can modulate UAF-1-dependent RNA splicing and suggest that RBM5 might interact with U2AF large subunit to affect tumor formation.

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Tumor suppressor RBM5 directly interacts with the DExD/H‐box protein DHX15 and stimulates its helicase activity

Cited by 58 publications

References 25 publications

RBM5 promotes exon 4 skipping of AID pre‐mRNA by competing with the binding of U2AF65 to the polypyrimidine tract

RBM5 promotes exon 4 skipping of AID pre‐mRNA by competing with the binding of U2AF65 to the polypyrimidine tract

Molecular alterations in areas generating fast ripples in an animal model of temporal lobe epilepsy

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

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