| Expression of MLL peaks at boundary of G1/S and G2/M phases, necessary to enter the S phase and progression into mitosis, respectively. Two major E3 complexes SCFSkp2 and APCCdc20 ensure MLL’s degradation through the cell cycle, regulating its expression at specific stages as required [107]. Taspase 1-mediated cleavage is another post-translational modification required for the MLL/MLL2 to control cell cycle. MLL is proteolytically cleaved by Taspase 1 to generate a fully functional mature MLLN320/C180 heterodimer [74]. Following cleavage by Taspase 1, MLL/MLL2 target to cyclin promoters to methylate histone H3K4, leading to the activation of genes involved in cell cycle regulation [74]. However, in contrast to this observation, another in vivo study on mouse indicates that MLL-dependent gene activation is independent of Taspase 1-mediated proteolytic cleavage, and rather depends on the intramolecular interaction between the MLLC and MLLN subunits [108]. Upon loss of intra-molecular interaction, FYRN domain is exposed which engenders MLL degradation resulting in loss of its function [108]. MLL and H3K4 methylation, both regulate the cell cycle in a distinct and dynamic manner, and play significant roles in the differential expression of Hox genes (HoxA5, HoxA7 and HoxA10) associated with cell cycle regulation [109]. MLL, normally associates with euchromatin at G1 phase, detaches from condensed mitotic chromatin followed by re-association towards the late telophase. Distinct to this observation, H3K4 trimethylation mark remains associated with chromatin throughout the cell cycle [109]. Contrary to this study, Blobel et.al. reported that MLL occupies chromatin throughout mitosis [110]. They also demonstrated that MLL recruits Menin, Ash2L, RbBP5 to mitotic chromatin and thus, ensures rapid onset of transcriptional activities following completion of mitosis [110]. |
