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The PHD3 domain of MLL acts as a CYP33-regulated switch between MLL-mediated activation and repression

Sangho Park1, Ute Osmers, Gayathree Raman

  • 1Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908, USA.

Biochemistry
|August 4, 2010
PubMed

Insights

The mixed lineage leukemia (MLL) gene

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • The mixed lineage leukemia (MLL) gene is crucial for epigenetic regulation and frequently involved in leukemia-causing translocations.
  • Loss of the MLL plant homeodomain 3 (PHD3) in MLL fusion proteins is linked to leukemia, and its reinsertion reduces transforming activity.

Purpose of the Study:

  • To investigate the interaction between MLL PHD3 and human nuclear Cyclophilin33 (CYP33) RRM domain.
  • To elucidate the mechanism by which CYP33 and PHD3 regulate MLL target gene expression and epigenetic marks.

Main Methods:

  • Structural characterization of PHD3 and CYP33 RRM domains.
  • Analysis of binding interactions between PHD3, CYP33 RRM, and histone peptides.
  • Assay of CYP33 proline isomerase activity on histone peptides.

Main Results:

  • CYP33 binding to PHD3 and H3K4me3 binding to PHD3 are mutually inhibitory, indicating PHD3 acts as a molecular switch.
  • CYP33 binding to PHD3 mediates downregulation of MLL target genes (HOXC8, HOXA9, CDKN1B, C-MYC).
  • This downregulation correlates with reduced H3K4me3 and histone acetylation levels.

Conclusions:

  • The MLL PHD3 domain functions as a molecular switch controlling gene activation and repression.
  • CYP33's proline isomerase activity and its interaction with PHD3 provide a mechanism for MLL-mediated gene repression.

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