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PreprintCited 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·2024·Nucleic Acids Research
DOI 10.1101/2024.10.19.619198PMC PMC12956345

Preprint — published as 10.1093/nar/gkag181 · Paper page

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Abstract

N-myc is a member of the myc family of transcription factors, which are powerful drivers of cellular growth and consequently, important oncoproteins. N-myc interacts with many factors and complexes to affect transcription. One such complex is the RNA Polymerase III assembly factor, TFIIIC, a six-member 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 largely 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, which suggests that TFIIIC5 is at most a secondary binding site for DNA. Here we identified the DNA binding domain of TFIIIC5 as a key binding site for N-myc. We used an integrated approach combining NMR, HDX mass spectrometry, pull-downs and biophysical assays to elucidate the molecular basis of the interaction. Two sequences in the transactivation domain of N-myc bind to the DNA binding interface of TFIIIC5. AlphaFold modelling predicts a high-confidence 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. The same two motifs in N-myc also interact with Aurora-A kinase, which competes with N-myc for TFIIIC binding during S-phase. This model elucidates how the N-myc:TFIIIC5 interaction competes with other interactions, providing a basis for their mutual censoring function and regulation. GRAPHICAL ABSTRACT:

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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
openRxiv
Published
2024-10-20
Volume
54
Issue
5
ISSN
0305-1048 (ISSN-L)
DOI
10.1101/2024.10.19.619198
PMC
PMC12956345
OpenAlex
W7131890998
Cited by
3
References
1
Citations by year
2026: 3
FWCI
6.09
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
  • Wellcome Trust (220628/Z/20/Z, 104920/Z/14/Z, 094232/Z/10/Z)
  • Royal Society (220628/Z/20/Z)
  • University of Leeds
  • Medical Research Council (MC_PC_MR/Y002482/1, MR/V029975/1)
  • Biotechnology and Biological Sciences Research Council (BB/V003577/2, BB/M012573/1, BB/V003577/1)
  • 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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