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Structural basis for the FOXM1 DNA binding domain to specific dsDNA substrate

Mingxuan Sun1, Lei Wang1, Jing Cui1

  • 1Hefei National Research Center for Cross disciplinary Science, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.

Acta Biochimica Et Biophysica Sinica
|March 27, 2026
PubMed

Insights

Forkhead box protein M1 (FOXM1) is a cancer-driving transcription factor. Its DNA-binding domain structure reveals how it recognizes DNA, crucial for understanding cancer proliferation and therapy resistance.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • Forkhead box protein M1 (FOXM1) is a critical transcription factor.
  • FOXM1 overexpression drives cancer proliferation and therapy resistance.
  • FOXM1 recognizes DNA via its DNA-binding domain (DBD) and a specific FKH motif.

Purpose of the Study:

  • To determine the high-resolution crystal structure of the FOXM1-DBD bound to DNA.
  • To elucidate the molecular mechanism of FOXM1-DNA recognition.
  • To understand the role of FOXM1 in cancer cell proliferation and gene regulation.

Main Methods:

  • X-ray crystallography to obtain the FOXM1-DBD-DNA complex structure.
  • Structure-guided mutagenesis of key DNA-interacting residues.
  • Isothermal titration calorimetry (ITC) and electrophoretic mobility shift assay (EMSA) for biophysical validation.

Main Results:

  • The crystal structure reveals the FOXM1-DBD adopts a winged-helix fold, with alpha-helix 3 inserting into the DNA major groove.
  • An essential triad (Asn283, Arg286, His287) within alpha-helix 3 mediates sequence-specific DNA binding through hydrogen bonds and hydrophobic interactions.
  • Mutagenesis and biophysical assays confirmed the functional importance of these residues and revealed position-dependent base substitution tolerance within the FKH motif.

Conclusions:

  • The study provides a structural basis for FOXM1's DNA recognition mechanism.
  • Key residues and their interactions within the FOXM1-DBD are critical for selective genomic target binding.
  • Understanding FOXM1's DBD function offers insights into its role in cancer and potential therapeutic strategies.
Keywords:
DNA-binding domainFOXM1crystal structureprotein-dsDNA bindingtranscription factor

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