Molecular basis of FIR-mediated c-myc transcriptional control

Cukier, C.D.; Hollingworth, David; Martin, Stephen R.; Kelly, Geoff; Dı́az-Moreno, Irene; Ramos, Andrés

doi:10.1038/nsmb.1883

Cited by 58 publications

(72 citation statements)

References 42 publications

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“…4e6 As transcription intensifies, the melted DNA bubble at FUSE expands upstream, allowing the recruitment of FIR via DNA-protein interactions and protein-protein interaction between a shallow groove in FIR RNA recognition motif 2 and the most NH 2 terminal a-helix of FBP ( Figure 10, A and B). 22,23,54,55 FIR then restores TFIIH helicase activity to basal levels, depressing transcription. 7 Falling levels of supercoiling combined with Figure 10 Scheme for FBP operating as a molecular cruise control to help set MYC levels and to constrain fluctuations around the set point.…”

Section: Discussionmentioning

confidence: 99%

“…7,24 FBP, FBP2, and FBP3 have three, four, and two tyrosine-rich motifs, respectively. 14,24 The amino termini of FBP and FBP2 include an a-helix that interacts with RNA recognition motif 2 domain of FIR, 2,4,7,16,23 whereas an A/V substitution in FBP3 precludes this interaction. 16 A variety of in vitro and tissue culture experiments have associated FBP binding with a complex set of DNA and RNA targets.…”

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confidence: 99%

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Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Zhou

Chung

Castellar

et al. 2016

The American Journal of Pathology

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The transcription factor far upstream element binding protein (FBP) binds and activates the MYC promoter when far upstream element is via TFIIH helicase activity early in the transcription cycle. The fundamental biology and pathology of FBP are complex. In some tumors FBP seems pro-oncogenic, whereas in others it is a tumor suppressor. We generated an FBP knockout (Fubp1 À/À ) mouse to study FBP deficiency. FBP is embryo lethal from embryonic day 10.5 to birth. A spectrum of pathology is associated with FBP loss; besides cerebral hyperplasia and pulmonary hypoplasia, pale livers, hypoplastic spleen, thymus, and bone marrow, cardiac hypertrophy, placental distress, and small size were all indicative of anemia. Immunophenotyping of hematopoietic cells in wild-type versus knockout livers revealed irregular trilineage anemia, with deficits in colony formation. Despite normal numbers of hematopoietic stem cells, transplantation of Fubp1 À/À hematopoietic stem cells into irradiated mice entirely failed to reconstitute hematopoiesis. In competitive transplantation assays against wild-type donor bone marrow, Fubp1 À/À hematopoietic stem cells functioned only sporadically at a low level. Although cultures of wild-type mouse embryo fibroblasts set Myc levels precisely, Myc levels of mouse varied wildly between fibroblasts harvested from different Fubp1 À/À embryos, suggesting that FBP contributes to Myc set point fixation. FBP helps to hold multiple physiologic processes to close tolerances, at least in part by constraining Myc expression. The transcription factor Myc plays a decisive role in cell growth, differentiation, and senescence and so must be highly regulated. The far upstream element (FUSE) binding protein (FBP) binds single-stranded DNA of FUSE 1.7 kb upstream of the major P2 promoter of the human MYC gene. 1e3 FUSE melting in response to dynamic supercoils propagated from the MYC promoters enables FBP binding. FBP activates TFIIH helicase activity to accelerate the transcription cycle from preinitiation complex assembly through promoter escape and onto pause release. 4e6 Positive regulation of MYC is at least in part counteracted by FBP interacting repressor (FIR) that binds FBP and FUSE and opposes TFIIH helicase activity, retarding the transcription cycle. 5,7 Besides MYC, FBP regulates the expression of the cyclin-dependent kinase inhibitor p21, stathmin, and USP29, a powerful stabilizer of p53 induced by oxidative stress. 8e10 Because the FBP/FIR system reads single-stranded DNA sequences exposed by transcriptionally generated dynamic supercoiling, it is proposed that the FBP/ FIR/FUSE system serves as a molecular cruise control that monitors the mechanical output of promoters in real time while providing both positive and negative feedback. 11e13Supported by the NIH

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Zhou

Chung

Castellar

et al. 2016

The American Journal of Pathology

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“…60 On the other hand, in FBP-Interacting Repressor (FIR) protein, the a-helix face of RRM1 packs onto the b-sheet face of RRM2, creating a stable interface. 61,62 Examples of Trp-mediated homodimerization in other RRM domains have been previously reported, as in the Nup35 protein. 63 In contrast, the RRM modules of the splicing factor Pub60 form a dimeric interface driven by electrostatic interactions involving a flexible loop.…”

Section: Discussionmentioning

confidence: 99%

The C-terminal RNA binding motif of HuR is a multi-functional domain leading to HuR oligomerization and binding to U-rich RNA targets

et al. 2014

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“…SAP155 somatic mutations observed in cancers accumulated at a specific site, supporting a gain-of-function of SAP155, and perhaps strengthening binding with FIR or FIRDexon2. The FBP-FIR-FUSE system mediates c-myc transcriptional control because the RNA recognition motifs of FIR provide a platform for independent FUSE DNA and FBP protein binding, and this explains the structural basis of the reversibility of the FBP-FIR interaction (32,33). Does FIRDexon2 interfere with the dimerization of FIR on nucleic acid binding?…”

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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Molecular basis of FIR-mediated c-myc transcriptional control

Cited by 58 publications

References 42 publications

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

The C-terminal RNA binding motif of HuR is a multi-functional domain leading to HuR oligomerization and binding to U-rich RNA targets

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

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