Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression

He, Liusheng; Liu, Juhong; Collins, Irene; Sanford, Suzanne; O’Connell, Brian; Benham, Craig J.; Levens, David

doi:10.1093/emboj/19.5.1034

Cited by 143 publications

(160 citation statements)

References 53 publications

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“…Notably, immediately upon cessation of transcription, the naked DNA template in this system relaxed fully. Transcription-dependent melting of the far upstream element (FUSE) of the human MYC promoter was seen when this element was included in the excised segment, just as previously hypothesized (He et al 2000). Such transcription-dependent melting licensed the binding to FUSE of FUSE binding protein (FBP) and FBP interacting repressor (FIR) in vitro (Liu et al 2006).…”

Section: Dynamic Supercoils-in Vitrosupporting

confidence: 53%

Controlling gene expression by DNA mechanics: emerging insights and challenges

2016

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Transcription initiation is a major control point for the precise regulation of gene expression. Our knowledge of this process has been mainly derived from protein-centric studies wherein cis-regulatory DNA sequences play a passive role, mainly in arranging the protein machinery to coalesce at the transcription start sites of genes in a spatial and temporal-specific manner. However, this is a highly dynamic process in which molecular motors such as RNA polymerase II (RNAPII), helicases, and other transcription factors, alter the level of mechanical force in DNA, rather than simply a set of static DNA-protein interactions. The double helix is a fiber that responds to flexural and torsional stress, which if accumulated, can affect promoter output as well as change DNA and chromatin structure. The relationship between DNA mechanics and the control of early transcription initiation events has been under-investigated. Genomic techniques to display topological stress and conformational variation in DNA across the mammalian genome provide an exciting new insight on the role of DNA mechanics in the early stages of the transcription cycle. Without understanding how torsional and flexural stresses are generated, transmitted, and dissipated, no model of transcription will be complete and accurate.

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Section: Dynamic Supercoils-in Vitrosupporting

confidence: 53%

Controlling gene expression by DNA mechanics: emerging insights and challenges

2016

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“…After FIR represses transcription, the level of dynamic supercoiling falls, FUSE reanneals and FBP is released thus a pulse of expression is generated (9,14,24,26). If such pulse generation operates at other genes, revealing the chemical and structural principles that govern FBP binding at FUSE may facilitate prediction of other FBP targets.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo and in vitro binding studies have identified the span along the bottom strand of FUSE that binds FBP and have indicated the orientation of the bound protein (11,14). Although Braddock et al used NMR to solve the solution structure of an FBP fragment, KH-domains 3 ϩ 4, bound to a short segment of FUSE (15), the sequence contacts and structural context for DNA recognition by full length FBP across the full FUSE region remain unexplored, and less is known about the interactions of FBP and FIR with other genomic targets.…”

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confidence: 99%

Hierarchical mechanisms build the DNA-binding specificity of FUSE binding protein

Benjamin

Chung

Sanford

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The far upstream element (FUSE) binding protein (FBP), a singlestranded nucleic acid binding protein, is recruited to the c-myc promoter after melting of FUSE by transcriptionally generated dynamic supercoils. Via interactions with TFIIH and FBP-interacting repressor (FIR), FBP modulates c-myc transcription. Here, we investigate the contributions of FBP's 4 K Homology (KH) domains to sequence selectivity. EMSA and missing contact point analysis revealed that FBP contacts 4 separate patches spanning a large segment of FUSE. A SELEX procedure using paired KH-domains defined the preferred subsequences for each KH domain. Unexpectedly, there was also a strong selection for the noncontacted residues between these subsequences, showing that the contact points must be optimally presented in a backbone that minimizes secondary structure. Strategic mutation of contact points defined in this study disabled FUSE activity in vivo. Because the biological specificity of FBP is tuned at several layers: (i) accessibility of the site; (ii) supercoil-driven melting; (iii) presentation of unhindered bases for recognition; and (iv) modular interaction of KH-domains with cognate bases, the FBP-FIR system and sequence-specific, single-strand DNA binding proteins in general are likely to prove versatile tools for adjusting gene expression.DNA conformation ͉ KH-domain ͉ ssDNA sequence specificity

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“…Binding of FBP to FUSE is essential for c-myc transcription. Moreover, inhibition or loss of FBP function arrests cellular proliferation and abrogates c-myc expression (He et al, 2000a;Chung and Levens, 2005). Accordingly, we speculate that FBP proteins function as key regulators of the c-myc promoter.…”

Section: Introductionmentioning

confidence: 99%

Far upstream element-binding protein-1, a novel caspase substrate, acts as a cross-talker between apoptosis and the c-myc oncogene

et al. 2009

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Far upstream element-binding protein-1 (FBP-1) binds to an upstream element of the c-myc promoter and regulates the c-myc mRNA level. Earlier, FBP-1 was identified as a candidate substrate of caspase-7. Here, we report that FBP-1 is cleaved by executor caspases, both in vitro and during apoptosis. Cleavage occurs at the caspase consensus site (DQPD 74 ) located within the classical bipartite nuclear localization signal sequence. In cells subjected to apoptotic stimuli, the caspase-mediated cleavage of FBP-1 leads to its decreased presence in the nucleus, concomitant with the marked downregulation of c-Myc and its various target proteins. By contrast, cells transfected with a non-cleavable mutant of FBP-1 (D74A) maintain higher levels of c-Myc and are protected from apoptosis. On the basis of these results, we suggest that the oncogenic potential of c-Myc is 'switched off' after apoptosis induction as a consequence of the caspasemediated cleavage of FBP-1.

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Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression

Cited by 143 publications

References 53 publications

Controlling gene expression by DNA mechanics: emerging insights and challenges

Controlling gene expression by DNA mechanics: emerging insights and challenges

Hierarchical mechanisms build the DNA-binding specificity of FUSE binding protein

Far upstream element-binding protein-1, a novel caspase substrate, acts as a cross-talker between apoptosis and the c-myc oncogene

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