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Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression.

Cell | Jun 25, 2010

http://www.ncbi.nlm.nih.gov/pubmed/20541251

The MLL1 gene is a frequent target for recurrent chromosomal translocations, resulting in transformation of hematopoietic precursors into leukemia stem cells. Here, we report on structure-function studies that elucidate molecular events in MLL1 binding of histone H3K4me3/2 marks and recruitment of the cyclophilin CyP33. CyP33 contains a PPIase and a RRM domain and regulates MLL1 function through HDAC recruitment. We find that the PPIase domain of CyP33 regulates the conformation of MLL1 through proline isomerization within the PHD3-Bromo linker, thereby disrupting the PHD3-Bromo interface and facilitating binding of the MLL1-PHD3 domain to the CyP33-RRM domain. H3K4me3/2 and CyP33-RRM target different surfaces of MLL1-PHD3 and can bind simultaneously to form a ternary complex. Furthermore, the MLL1-CyP33 interaction is required for repression of HOXA9 and HOXC8 genes in vivo. Our results highlight the role of PHD3-Bromo cassette as a regulatory platform, orchestrating MLL1 binding of H3K4me3/2 marks and cyclophilin-mediated repression through HDAC recruitment.

Pubmed ID: 20541251 RIS Download

Mesh terms: Amino Acid Sequence | Cell Line | Crystallography, X-Ray | Cyclophilins | Histone Deacetylases | Histone-Lysine N-Methyltransferase | Histones | Humans | Methylation | Models, Molecular | Molecular Sequence Data | Myeloid-Lymphoid Leukemia Protein | Nuclear Magnetic Resonance, Biomolecular | Proline | Protein Interaction Domains and Motifs

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Associated grants

  • Agency: NCI NIH HHS, Id: K99 CA151683
  • Agency: NCI NIH HHS, Id: P30 CA008748

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