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Cited by 3Genomics and Chromatin DynamicsProtein Structure and DynamicsNuclear Structure and Function

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Mechanism of interaction between the transactivation domain of N-myc and the DNA-binding surface of TFIIIC5

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Leen, Eoin, Yeoh, Sharon, Sahak, Eka, Mitchell, Ellie, Wildsmith, Gemma, Batchelor, Matthew, Calabrese, Antonio N, Büchel, Gabriele, Bayliss, Richard·2026·Nucleic Acids Research
DOI 10.1093/nar/gkag181PMC PMC12956345

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Abstract

N-myc is a transcription factor, a powerful driver of cellular growth and an important oncoprotein. N-myc interacts with many factors, including the RNA Polymerase III assembly factor, TFIIIC, a six-subunit complex that is essential for the transcription of small, structured RNA. TFIIIC and N-myc mutually restrict each other’s chromatin association, and their complex contributes to quality control in mRNA transcription. We previously demonstrated that the intrinsically disordered transactivation domain of N-myc interacts directly with a sub-complex of TFIIIC, τA. Structural studies by others show that DNA binding of τA is largely mediated by TFIIIC3, leaving open the role of the DNA-binding domain of TFIIIC5. Here, we demonstrate that this domain is a binding site for two regions in the transactivation domain of N-myc, through an integrated approach combining NMR spectroscopy, hydrogen–deuterium exchange mass spectrometry, and interaction assays (pull-downs, ITC, fluorescence polarization, and co-immunoprecipitation). AlphaFold modelling predicts with high-confidence a binding mode for the higher affinity N-myc motif that overlaps with the predicted intramolecular binding site of the C-terminal acidic plug of TFIIIC5, removal of which enhances the binding of N-myc. This model elucidates how the N-myc:TFIIIC5 interaction competes with DNA and other interactions, providing a basis for their mutual regulation.

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Metadata

Authors
Leen, E., Yeoh, S., Sahak, E., Mitchell, E., Wildsmith, G., Batchelor, M., Calabrese, A. N., Büchel, G., & Bayliss, R.
Affiliations
  • University of Leeds (GB)
  • University of Würzburg (DE)
Corresponding author
  • Leen, Eoin
  • Bayliss, Richard
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2026-02-24
Volume
54
Issue
5
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkag181
PMC
PMC12956345
OpenAlex
W7131890998
Cited by
3
References
3
Citations by year
2026: 3
FWCI
6.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion, other-oa)
Funders
  • Medical Research Council (MR/V029975/1)
  • Mildred Scheel Junior Research Center Program
  • Biotechnology and Biological Sciences Research Council (BB/V003577/1, BB/V003577/2, BB/M012573/1)
  • Wellcome Trust (094232/Z/10/Z, 104920/Z/14/Z)
  • Royal Society (220628/Z/20/Z)
  • MRC World Class Labs (MC_PC_MR/Y002482/1)
  • University of Leeds
  • Oxford University Press
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
MYCN, TFIIIC, transactivation domain, protein-protein interaction, DNA-binding domain, RNA polymerase III, intrinsically disordered proteins, binding sites, oncoprotein, chromatin association
MeSH terms
Protein Domains, Transcription Factor TFIIIC, Binding Sites, DNA, Humans, Models, Molecular, Protein Binding, Transcriptional Activation, Proto-Oncogene Proteins c-myc, Transcription Factors, TFIII

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