A Cancer-Associated Missense Mutation in PP2A-Aα Increases Centrosome Clustering during Mitosis

Antao, Noelle V, Marcet-Ortega, Marina, Cifani, Paolo, Kentsis, Alex, Foley, Emily A (September 2019) A Cancer-Associated Missense Mutation in PP2A-Aα Increases Centrosome Clustering during Mitosis. iScience, 19. pp. 74-82. ISSN 2589-0042

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Abstract

Whole-genome doubling (WGD) is common early in tumorigenesis. WGD doubles ploidy and 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 to allow bipolar cell division. Cancer cells are often 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 "scaffolding" subunit of PP2A (PP2A-Aα), positively correlate with WGD. We introduced a heterozygous hotspot mutation, P179R, into PPP2R1A in human RPE-1 cells. PP2A-AαP179R decreases PP2A assembly and intracellular targeting in mitosis. Strikingly, PP2A-AαP179R enhances centrosome clustering when centrosome number is increased either by cytokinesis failure or centrosome amplification, likely through PP2A-Aα loss of function. Thus cancer-associated mutations in PP2A-Aα may increase cellular fitness after WGD by enhancing centrosome clustering.

Item Type:	Paper
Subjects:	diseases & disorders > cancer organs, tissues, organelles, cell types and functions > organelles, types and functions > mitosis bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
CSHL Authors:	Cifani, Paolo
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	September 2019
Date Deposited:	31 Jan 2023 19:07
Last Modified:	21 Nov 2024 19:21
PMCID:	PMC6664223
URI:	https://repository.cshl.edu/id/eprint/40818

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