title: A subset of mixed lineage leukemia proteins has plant homeodomain (PHD)-mediated E3 ligase activity.
abstract: The mixed lineage leukemia protein MLL1 contains four highly conserved plant homeodomain (PHD) fingers, which are invariably deleted in oncogenic MLL1 fusion proteins in human leukemia. Here we show that the second PHD finger (PHD2) of MLL1 is an E3 ubiquitin ligase in the presence of the E2-conjugating enzyme CDC34. This activity is conserved in the second PHD finger of MLL4, the closest homolog to MLL1 but not in MLL2 or MLL3. Mutation of PHD2 leads to MLL1 stabilization, as well as increased transactivation ability and MLL1 recruitment to the target gene loci, suggesting that PHD2 negatively regulates MLL1 activity.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Jingya
authors.initials: J
authors.lastname: Wang
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Muntean
authors.forename: Laura
authors.initials: L
authors.lastname: Wu
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability / Q000502:physiology; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C452979:KMT2C protein, human; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human; C577447:CDC34 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases