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Mixed Lineage Leukemia 5 (MLL5) Regulates Cell Cycle Progression and E2F1-responsive Gene Expression via Association with Host Cell Factor-1 (HCF-1)
Peipei Zhou1, Zhilong Wang1, Xiujie Yuan1, Cuihong Zhou1, Lulu Liu1, Xiaoling Wan1, Feng Zhang1, Xiaodan Ding1, Chuangui Wang2, Sidong Xiong3, Zhen Wang4, Jinduo Yuan4, Qiang Li5 and Yan Zhang1*
Trithorax group proteins methylate lysine 4 of histone3 (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 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 the 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.
