The MLL/WDR5 complex promotes midbody recruitment of KIF2C for microtubule depolymerization and furrow initiation...

Mixed-lineage leukemia protein (MLL, also known as KMT2A) is a well-characterized epigenetic regulator whose non-canonical activities remain underappreciated. MLL has been shown to localize to the midbody, and loss of this protein leads to binucleation. However, the crucial role of the MLL complex in midbody formation remains underexplored. Here, we further characterize the localization of MLL and its associated protein WDR5 to the midbody. Loss of the MLL/WDR5 complex results in defective formation of the midbody, which displays a wide midzone-like microtubule structure, along with chromosome bridges, resulting in binucleated cells. We show that MLL and WDR5 interact with the kinesin 13 motor KIF2C and target it to the midbody. The depolymerase activity of KIF2C promotes correct localization of the centralspindlin complex, compaction of midzone microtubules and, finally, timely furrow initiation. Thus, we identify a previously unrecognized role for MLL and KIF2C in cytokinesis regulation. Together with earlier findings, this implicates these proteins in regulation of the actin-microtubule cytoskeleton interface - a pathway frequently altered in oncogenesis.