Zhao et al. reveal that the prospective tumor suppressor MLL5 helps mitotic cells maintain a bipolar spindle by preventing the kinase PLK1 from aggregating in the cytosol.
MLL5, whose gene is often deleted in patients with acute myeloid leukemia, localizes to nuclear speckles and regulates chromatin organization and the cell cycle. During mitosis, cells lacking MLL5 form multipolar spindles with misaligned chromosomes, resulting in genomic instability. MLL5 promotes chromosome alignment by stabilizing the Aurora B kinase–containing chromosomal passenger complex, but how MLL5 limits the formation of multipolar spindles remains unknown.
Zhao et al. found that, in addition to nuclear speckles, MLL5 localizes to centrosomes throughout the cell cycle. During mitosis, MLL5 delocalized from chromatin and bound to PLK1, a key regulator of centrosome maturation that recruits and phosphorylates several microtubule-organizing proteins. In the absence of MLL5, PLK1’s localization to centrosomes was partially reduced, and the kinase also formed numerous aggregates dotted throughout the cytoplasm. Many of these aggregates recruited additional proteins, such as pericentrin and γ-tubulin, to form acentrosomal microtubule-organizing centers (aMTOCs) that contributed to the assembly of multipolar spindles.
The researchers discovered that a motif in MLL5’s central region binds to the polo-box domain of PLK1. Mutating this motif inhibited MLL5’s ability to prevent PLK1 aggregation and multipolar spindle formation. Senior author Lih-Wen Deng thinks that, by limiting PLK1 aggregation, cytosolic MLL5 enhances the kinase’s incorporation into centrosomes. She now wants to investigate how, in the absence of MLL5, PLK1 aggregates develop into aMTOCs.
Text by Ben Short