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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.

Original publication

DOI

10.1016/j.cell.2010.05.016

Type

Journal article

Journal

Cell

Publication Date

25/06/2010

Volume

141

Pages

1183 - 1194

Keywords

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