MLL5 maintains genomic integrity by regulating the stability of the chromosomal passenger complex through a...

Mixed lineage leukemia 5 (MLL5) is a versatile nuclear protein associated with many cellular events. We have shown previously that phosphorylation of MLL5 by Cdk1 is required for mitotic entry. In this paper, the function of MLL5 in mitotic regulation is further explored. SiRNA-mediated downregulation of MLL5 caused improper chromosome alignment at metaphase and resulted in failure of DNA segregation and cytokinesis. Mechanistic studies revealed that the chromosomal passenger complex (CPC), which plays a key role in chromosomal bi-orientation, was delocalized from the inner centromere region because of proteasome-mediated degradation in MLL5-depleted cells. Biochemical analyses further demonstrated that the central domain of MLL5 interacted with the C-terminus of Borealin, and the interaction is essential to maintain the stability of Borealin. Moreover, the mitotic defects in MLL5-depleted cells were rescued by overexpression of FLAG-MLL5, but not by a FLAG-MLL5 mutant that did not contain the central domain. Collectively, our results suggest that MLL5 functionally interacts with Borealin, facilitates the expression of CPC, and hence contributes to mitotic fidelity and genomic integrity.