title: A SET-domain-independent role of WRAD complex in cell-cycle regulatory function of mixed lineage leukemia.
abstract: MLL, the trithorax ortholog, is a well-characterized histone 3 lysine 4 methyltransferase that is crucial for proper regulation of the Hox genes during embryonic development. Chromosomal translocations, disrupting the Mll gene, lead to aggressive leukemia with poor prognosis. However, the functions of MLL in cellular processes like cell-cycle regulation are not well studied. Here we show that the MLL has a regulatory role during multiple phases of the cell cycle. RNAi-mediated knockdown reveals that MLL regulates S-phase progression and, proper segregation and cytokinesis during M phase. Using deletions and mutations, we narrow the cell-cycle regulatory role to the C subunit of MLL. Our analysis reveals that the transactivation domain and not the SET domain is important for the S-phase function of MLL. Surprisingly, disruption of MLL-WRAD interaction is sufficient to disrupt proper mitotic progression. These mitotic functions of WRAD are independent of SET domain of MLL and, therefore, define a new role of WRAD in subset of MLL functions. Finally, we address the overlapping and unique roles of the different SET family members in the cell cycle.
authors.affiliation: Laboratory of Cell Cycle Regulation, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad, India.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ali
authors.affiliation: Laboratory of Cell Cycle Regulation, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad, India.
authors.forename: Sailaja Naga
authors.initials: SN
authors.lastname: Veeranki
authors.affiliation: Laboratory of Cell Cycle Regulation, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad, India shweta@cdfd.org.in.
authors.forename: Shweta
authors.initials: S
authors.lastname: Tyagi
mesh_terms: D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D059585:G1 Phase Cell Cycle Checkpoints; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D061986:MCF-7 Cells; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D021122:Protein Subunits / Q000502:physiology; D016196:S Phase; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: C485622:ASH2L protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D021122:Protein Subunits; C470552:RBBP5 protein, human; D014157:Transcription Factors; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human