Requirement of PP2A-B56Par1 for the Stabilization of the CDK Inhibitor Rum1 and Activation of APC/CSte9 during Pre-Start G1 in S. pombe

Vilte Stonyte; Ruth Martín; Dario Segura-Peña; Nikolina Sekulić; Sandra Lopez-Aviles

doi:10.1016/j.isci.2020.101063

Requirement of PP2A-B56^Par1 for the Stabilization of the CDK Inhibitor Rum1 and Activation of APC/C^Ste9 during Pre-Start G1 in S. pombe

iScience. 2020 May 22;23(5):101063. doi: 10.1016/j.isci.2020.101063. Epub 2020 Apr 16.

Authors

Vilte Stonyte¹, Ruth Martín², Dario Segura-Peña¹, Nikolina Sekulić³, Sandra Lopez-Aviles⁴

Affiliations

¹ Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
² Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway. Electronic address: r.m.martin@ncmm.uio.no.
³ Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway; Department of Chemistry, University of Oslo, Oslo, Norway.
⁴ Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway; Department of Biosciences, University of Oslo, Oslo, Norway. Electronic address: sandra.lopez-aviles@ncmm.uio.no.

Abstract

Exit from the cell cycle during the establishment of quiescence and upon cell differentiation requires the sustained inactivation of CDK complexes. Fission yeast cells deprived of nitrogen halt cell cycle progression in pre-Start G1, before becoming quiescent or undergoing sexual differentiation. The CDK inhibitor Rum1 and the APC/C activator Ste9 are fundamental for this arrest, but both are down-regulated by CDK complexes. Here, we show that PP2A-B56^Par1 is instrumental for Rum1 stabilization and Ste9 activation. In the absence of PP2A-B56^Par1, cells fail to accumulate Rum1, and this results in persistent CDK activity, Ste9 inactivation, retention of the mitotic cyclin Cdc13, and impaired withdrawal from the cell cycle during nitrogen starvation. Importantly, mutation of a putative B56 interacting motif in Rum1 recapitulates these defects. These results underscore the relevance of CDK-counteracting phosphatases in cell differentiation, establishment of the quiescent state, and escape from it in cancer cells.

Keywords: Biochemistry; Biological Sciences; Cell Biology.