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Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation.

Van Roey K, Davey NE - Cell Commun. Signal (2015)

Bottom Line: Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms.In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules.Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules.

View Article: PubMed Central - PubMed

Affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117, Heidelberg, Germany. roey@embl.de.

ABSTRACT
A substantial portion of the regulatory interactions in the higher eukaryotic cell are mediated by simple sequence motifs in the regulatory segments of genes and (pre-)mRNAs, and in the intrinsically disordered regions of proteins. Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms. The ease of motif acquisition simplifies access to basal housekeeping functions, facilitates the co-regulation of multiple biomolecules allowing them to respond in a coordinated manner to changes in the cell state, and supports the integration of multiple signals for combinatorial decision-making. Consequently, motifs are indispensable for temporal, spatial, conditional and basal regulation at the transcriptional, post-transcriptional and post-translational level. In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules. We discuss how co-operativity allows simple static motifs to perform the conditional regulation that underlies decision-making in higher eukaryotic biological systems. We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules.

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Modular architecture of p21 gene, pre-mRNA and protein, showing known functional modules (see Table 2). a The p21 gene contains: two p53-responsive elements [159, 160]; four E-box motifs for binding Transcription factor AP-4 [161]; retinoid X response [162], retinoid acid response [163] and Vitamin D response [164] elements; three STAT-binding elements that recruit STAT1, STAT3 and STAT5 dimers [165, 166]; three CDX-binding sites that bind homeobox protein CDX-2 [167]; a T-element that binds the T-box transcription factor TBX2 [168]; a binding site for CCAAT/enhancer-binding protein beta [169]; six Sp1-binding sites [170–173]; a site for binding Transcription factor AP-2-alpha [174]; sites for Transcription factor E2F1 [175]; a Forkhead-binding site for Forkhead box protein P3 [176]. b The p21 (pre-)mRNA contains: AU-rich elements in the 3′-UTR for binding ELAV-like protein 4 [177], ELAV-like protein 1 [178], and RNA-binding protein 38 [179]; a binding site for RNA-binding protein Musashi homolog 1 [180]; GC-rich sequence binding CUGBP Elav-like family member 1 and calreticulin (CRT) [148]; CU-rich sequence in the 3′-UTR for binding heterogeneous nuclear ribonucleoprotein K [181]; splice donor and acceptor site for recruitment of the spliceosome machinery for intron removal. ORF: open reading frame. c The p21 protein contains: the intrinsically disordered Cyclin-dependent Kinase Inhibitor (CKI) region [182]; a PIP degron recruiting Denticleless protein homolog [183, 184]; a D box for docking to the Cell division cycle protein 20 homolog subunit of the APC/C [185]; a PIP box for docking to the DNA polymerase delta processivity factor PCNA [142, 186]; one N-terminal and one C-terminal RxL Cyclin docking motif for binding to the Cyclin E subunit of the Cyclin E-Cdk2 kinase complex [187, 188]; an NLS for recruitment to the nuclear import machinery [189]; a modification motif for phosphorylation at T145 by PKB [190, 191]; a modification motif for phosphorylation at S146 by nuclear-Dbf2-related (NDR) kinases [192]; a modification motif for phosphorylation at S130 by Cyclin E-Cdk2 kinase complex [193, 194]
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Fig4: Modular architecture of p21 gene, pre-mRNA and protein, showing known functional modules (see Table 2). a The p21 gene contains: two p53-responsive elements [159, 160]; four E-box motifs for binding Transcription factor AP-4 [161]; retinoid X response [162], retinoid acid response [163] and Vitamin D response [164] elements; three STAT-binding elements that recruit STAT1, STAT3 and STAT5 dimers [165, 166]; three CDX-binding sites that bind homeobox protein CDX-2 [167]; a T-element that binds the T-box transcription factor TBX2 [168]; a binding site for CCAAT/enhancer-binding protein beta [169]; six Sp1-binding sites [170–173]; a site for binding Transcription factor AP-2-alpha [174]; sites for Transcription factor E2F1 [175]; a Forkhead-binding site for Forkhead box protein P3 [176]. b The p21 (pre-)mRNA contains: AU-rich elements in the 3′-UTR for binding ELAV-like protein 4 [177], ELAV-like protein 1 [178], and RNA-binding protein 38 [179]; a binding site for RNA-binding protein Musashi homolog 1 [180]; GC-rich sequence binding CUGBP Elav-like family member 1 and calreticulin (CRT) [148]; CU-rich sequence in the 3′-UTR for binding heterogeneous nuclear ribonucleoprotein K [181]; splice donor and acceptor site for recruitment of the spliceosome machinery for intron removal. ORF: open reading frame. c The p21 protein contains: the intrinsically disordered Cyclin-dependent Kinase Inhibitor (CKI) region [182]; a PIP degron recruiting Denticleless protein homolog [183, 184]; a D box for docking to the Cell division cycle protein 20 homolog subunit of the APC/C [185]; a PIP box for docking to the DNA polymerase delta processivity factor PCNA [142, 186]; one N-terminal and one C-terminal RxL Cyclin docking motif for binding to the Cyclin E subunit of the Cyclin E-Cdk2 kinase complex [187, 188]; an NLS for recruitment to the nuclear import machinery [189]; a modification motif for phosphorylation at T145 by PKB [190, 191]; a modification motif for phosphorylation at S146 by nuclear-Dbf2-related (NDR) kinases [192]; a modification motif for phosphorylation at S130 by Cyclin E-Cdk2 kinase complex [193, 194]

Mentions: Ultimately, tens to hundreds of modules in DNA, RNA and proteins, many of them motifs, regulate the life cycle of every gene product on the transcriptional, post-transcriptional and post-translational levels from transcription to degradation (Table 2, Fig. 4) [119].Fig. 4


Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation.

Van Roey K, Davey NE - Cell Commun. Signal (2015)

Modular architecture of p21 gene, pre-mRNA and protein, showing known functional modules (see Table 2). a The p21 gene contains: two p53-responsive elements [159, 160]; four E-box motifs for binding Transcription factor AP-4 [161]; retinoid X response [162], retinoid acid response [163] and Vitamin D response [164] elements; three STAT-binding elements that recruit STAT1, STAT3 and STAT5 dimers [165, 166]; three CDX-binding sites that bind homeobox protein CDX-2 [167]; a T-element that binds the T-box transcription factor TBX2 [168]; a binding site for CCAAT/enhancer-binding protein beta [169]; six Sp1-binding sites [170–173]; a site for binding Transcription factor AP-2-alpha [174]; sites for Transcription factor E2F1 [175]; a Forkhead-binding site for Forkhead box protein P3 [176]. b The p21 (pre-)mRNA contains: AU-rich elements in the 3′-UTR for binding ELAV-like protein 4 [177], ELAV-like protein 1 [178], and RNA-binding protein 38 [179]; a binding site for RNA-binding protein Musashi homolog 1 [180]; GC-rich sequence binding CUGBP Elav-like family member 1 and calreticulin (CRT) [148]; CU-rich sequence in the 3′-UTR for binding heterogeneous nuclear ribonucleoprotein K [181]; splice donor and acceptor site for recruitment of the spliceosome machinery for intron removal. ORF: open reading frame. c The p21 protein contains: the intrinsically disordered Cyclin-dependent Kinase Inhibitor (CKI) region [182]; a PIP degron recruiting Denticleless protein homolog [183, 184]; a D box for docking to the Cell division cycle protein 20 homolog subunit of the APC/C [185]; a PIP box for docking to the DNA polymerase delta processivity factor PCNA [142, 186]; one N-terminal and one C-terminal RxL Cyclin docking motif for binding to the Cyclin E subunit of the Cyclin E-Cdk2 kinase complex [187, 188]; an NLS for recruitment to the nuclear import machinery [189]; a modification motif for phosphorylation at T145 by PKB [190, 191]; a modification motif for phosphorylation at S146 by nuclear-Dbf2-related (NDR) kinases [192]; a modification motif for phosphorylation at S130 by Cyclin E-Cdk2 kinase complex [193, 194]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4666095&req=5

Fig4: Modular architecture of p21 gene, pre-mRNA and protein, showing known functional modules (see Table 2). a The p21 gene contains: two p53-responsive elements [159, 160]; four E-box motifs for binding Transcription factor AP-4 [161]; retinoid X response [162], retinoid acid response [163] and Vitamin D response [164] elements; three STAT-binding elements that recruit STAT1, STAT3 and STAT5 dimers [165, 166]; three CDX-binding sites that bind homeobox protein CDX-2 [167]; a T-element that binds the T-box transcription factor TBX2 [168]; a binding site for CCAAT/enhancer-binding protein beta [169]; six Sp1-binding sites [170–173]; a site for binding Transcription factor AP-2-alpha [174]; sites for Transcription factor E2F1 [175]; a Forkhead-binding site for Forkhead box protein P3 [176]. b The p21 (pre-)mRNA contains: AU-rich elements in the 3′-UTR for binding ELAV-like protein 4 [177], ELAV-like protein 1 [178], and RNA-binding protein 38 [179]; a binding site for RNA-binding protein Musashi homolog 1 [180]; GC-rich sequence binding CUGBP Elav-like family member 1 and calreticulin (CRT) [148]; CU-rich sequence in the 3′-UTR for binding heterogeneous nuclear ribonucleoprotein K [181]; splice donor and acceptor site for recruitment of the spliceosome machinery for intron removal. ORF: open reading frame. c The p21 protein contains: the intrinsically disordered Cyclin-dependent Kinase Inhibitor (CKI) region [182]; a PIP degron recruiting Denticleless protein homolog [183, 184]; a D box for docking to the Cell division cycle protein 20 homolog subunit of the APC/C [185]; a PIP box for docking to the DNA polymerase delta processivity factor PCNA [142, 186]; one N-terminal and one C-terminal RxL Cyclin docking motif for binding to the Cyclin E subunit of the Cyclin E-Cdk2 kinase complex [187, 188]; an NLS for recruitment to the nuclear import machinery [189]; a modification motif for phosphorylation at T145 by PKB [190, 191]; a modification motif for phosphorylation at S146 by nuclear-Dbf2-related (NDR) kinases [192]; a modification motif for phosphorylation at S130 by Cyclin E-Cdk2 kinase complex [193, 194]
Mentions: Ultimately, tens to hundreds of modules in DNA, RNA and proteins, many of them motifs, regulate the life cycle of every gene product on the transcriptional, post-transcriptional and post-translational levels from transcription to degradation (Table 2, Fig. 4) [119].Fig. 4

Bottom Line: Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms.In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules.Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules.

View Article: PubMed Central - PubMed

Affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117, Heidelberg, Germany. roey@embl.de.

ABSTRACT
A substantial portion of the regulatory interactions in the higher eukaryotic cell are mediated by simple sequence motifs in the regulatory segments of genes and (pre-)mRNAs, and in the intrinsically disordered regions of proteins. Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms. The ease of motif acquisition simplifies access to basal housekeeping functions, facilitates the co-regulation of multiple biomolecules allowing them to respond in a coordinated manner to changes in the cell state, and supports the integration of multiple signals for combinatorial decision-making. Consequently, motifs are indispensable for temporal, spatial, conditional and basal regulation at the transcriptional, post-transcriptional and post-translational level. In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules. We discuss how co-operativity allows simple static motifs to perform the conditional regulation that underlies decision-making in higher eukaryotic biological systems. We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules.

Show MeSH