PP2A-B55 phosphatase counteracts Ki-67-dependent chromosome individualization during mitosis

Abstract

Chromosome clustering; Mitosis; Phosphatase

Agrupamiento cromosómico; Mitosis; Fosfatasa

Agrupament cromosòmic; Mitosi; Fosfatasa

Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.

We thank Dr. Imamoto (RIKEN, Japan) and Ana Losada (CNIO, Spain) for providing antibodies. M.S.-F. was supported by the FPU Program from the Spanish Agencia Estatal de Investigación (AEI) of the Ministry of Science and Innovation. M.A.-F. was supported by the Asociación Española contra el Cáncer ( AECC; 2019/INVES19001ALVA ). M.R.-T. was supported by AECC ( POSTD211362RUIZ ). Research in the laboratory of D.W.G. is supported by the Austrian Academy of Sciences, the Vienna Science and Technology Fund (WWTF; projects LS17-003 and LS19-001 ), and the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (grant agreement 101019039 ). Work in the M.M. laboratory was supported by grants from the AEI-MICIIN ( RTI2018-095582-B-I00 and PID2021-1287260-B-100 ), the iLUNG2 Program ( S2022/BMD-7437 ) from the Comunidad de Madrid, and the iDIFFER Network of Excellence ( RED2022-134792-T ). VHIO acknowledges the Cellex Foundation for providing research facilities and equipment and the CERCA Program from the Generalitat de Catalunya for support. CNIO and VHIO are Severo Ochoa Centers of Excellence ( AEI-MICIU CEX2019-000891-S and CEX2020-001024-S/AEI/10.13039/501100011033 ).