title: Mixed lineage leukemia 5 (MLL5) protein regulates cell cycle progression and E2F1-responsive gene expression via association with host cell factor-1 (HCF-1).
abstract: Trithorax group proteins methylate lysine 4 of histone 3 (H3K4) at active gene promoters. MLL5 protein, a member of the Trithorax protein family, has been implicated in the control of the cell cycle progression; however, the underlying molecular mechanism(s) have not been fully determined. In this study, we found that the MLL5 protein can associate with the cell cycle regulator "host cell factor" (HCF-1). The interaction between MLL5 and HCF-1 is mediated by the "HCF-1 binding motif" (HBM) of the MLL5 protein and the Kelch domain of the HCF-1 protein. Confocal microscopy showed that the MLL5 protein largely colocalized with HCF-1 in the nucleus. Knockdown of MLL5 resulted in reduced cell proliferation and cell cycle arrest in the G1 phase. Moreover, down-regulation of E2F1 target gene expression and decreased H3K4me3 levels at E2F1-responsive promoters were observed in MLL5 knockdown cells. Additionally, the core subunits, including ASH2L, RBBP5, and WDR5, that are necessary for effective H3K4 methyltransferase activities of the Trithorax protein complexes, were absent in the MLL5 complex, suggesting that a distinct mechanism may be used by MLL5 for exerting its H3K4 methyltransferase activity. Together, our findings demonstrate that MLL5 could associate with HCF-1 and then be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation, thereby facilitating the cell cycle G1 to S phase transition.
authors: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
authors: Peipei
authors: P
authors: Zhou
authors: Zhilong
authors: Z
authors: Wang
authors: Xiujie
authors: X
authors: Yuan
authors: Cuihong
authors: C
authors: Zhou
authors: Lulu
authors: L
authors: Liu
authors: Xiaoling
authors: X
authors: Wan
authors: Feng
authors: F
authors: Zhang
authors: Xiaodan
authors: X
authors: Ding
authors: Chuangui
authors: C
authors: Wang
authors: Sidong
authors: S
authors: Xiong
authors: Zhen
authors: Z
authors: Wang
authors: Jinduo
authors: J
authors: Yuan
authors: Qiang
authors: Q
authors: Li
authors: Yan
authors: Y
authors: Zhang
mesh_terms: D000595:Amino Acid Sequence; D002453:Cell Cycle; D002467:Cell Nucleus; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051863:Host Cell Factor C1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D013058:Mass Spectrometry; D008745:Methylation; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D010449:Peptide Mapping; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C485622:ASH2L protein, human; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C497692:HCFC1 protein, human; D006657:Histones; D051863:Host Cell Factor C1; D047908:Intracellular Signaling Peptides and Proteins; C460660:KMT2E protein, human; D009687:Nuclear Proteins; C470552:RBBP5 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; C502547:WDR5 protein, human; D011495:Histone-Lysine N-Methyltransferase
keywords: Cell Cycle; E2F Transcription Factor; Epigenetics; Gene Expression; H3K4; HCF-1; Histone Methylation; MLL5; Trithorax
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