FAM122A ensures cell cycle interphase progression and checkpoint control by inhibiting B55α/PP2A through helical motifs

Jason S. Wasserman, Bulat Faezov, Kishan R. Patel, Alison M. Kurimchak, Seren M. Palacio, David J. Glass, Holly Fowle, Brennan C. McEwan, Qifang Xu, Ziran Zhao, Lauren Cressey, Neil Johnson, James S. Duncan, Arminja N. Kettenbach, Roland L. Dunbrack, Xavier Graña

Research output: Contribution to journalArticlepeer-review

Abstract

The Ser/Thr protein phosphatase 2 A (PP2A) regulates the dephosphorylation of many phosphoproteins. Substrate recognition are mediated by B regulatory subunits. Here, we report the identification of a substrate conserved motif [RK]-V-x-x-[VI]-R in FAM122A, an inhibitor of B55α/PP2A. This motif is necessary for FAM122A binding to B55α, and computational structure prediction suggests the motif, which is helical, blocks substrate docking to the same site. In this model, FAM122A also spatially constrains substrate access by occluding the catalytic subunit. Consistently, FAM122A functions as a competitive inhibitor as it prevents substrate binding and dephosphorylation of CDK substrates by B55α/PP2A in cell lysates. FAM122A deficiency in human cell lines reduces the proliferation rate, cell cycle progression, and hinders G1/S and intra-S phase cell cycle checkpoints. FAM122A-KO in HEK293 cells attenuates CHK1 and CHK2 activation in response to replication stress. Overall, these data strongly suggest that FAM122A is a short helical motif (SHeM)-dependent, substrate-competitive inhibitor of B55α/PP2A that suppresses multiple functions of B55α in the DNA damage response and in timely progression through the cell cycle interphase.

Original languageEnglish
Article number5776
Pages (from-to)5776
JournalNature Communications
Volume15
Issue number1
DOIs
StatePublished - Jul 10 2024

Keywords

  • Checkpoint Kinase 2/metabolism
  • Phosphorylation
  • Protein Phosphatase 2/metabolism
  • Cell Proliferation
  • Checkpoint Kinase 1/metabolism
  • Interphase
  • Humans
  • HEK293 Cells
  • Protein Binding
  • Cell Cycle Checkpoints/genetics
  • Amino Acid Motifs

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