A cancer-associated missense mutation in PP2A-Aα increases centrosome clustering during mitosis

A single incidence of whole-genome doubling (WGD) is common early in tumorigenesis. In addition to increasing ploidy, WGD doubles centrosome number. In the ensuing mitoses, excess centrosomes form a multipolar spindle, resulting in a lethal multipolar cell division. To survive, cells must cluster centrosomes into two poles to allow a bipolar cell division. Cancer cells are typically more proficient at centrosome clustering than untransformed cells, but the mechanism behind increased clustering ability is not well understood. Heterozygous missense mutations in PPP2R1A, which encodes the alpha isoform of the A-subunit of protein phosphatase 2A (PP2A-A), positively correlate with WGD. To understand this correlation, we introduced a heterozygous hotspot mutation, P179R, in endogenous PP2A-A in human tissue culture cells. We find that PP2A-AP179R decreases PP2A assembly and targeting. Strikingly, when centrosome number is increased, either through cytokinesis failure or centrosome amplification, PP2A-A mutant cells are more proficient than WT cells at centrosome clustering, likely due to PP2A-A loss-of-function. PP2A-AP179R appears to enhance centrosome clustering by altering the interactions between centrosomes and the cell cortex. Thus, cancer-associated mutations in PP2A-A may increase cellular fitness after WGD by enhancing centrosome clustering.