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

Jason S Wasserman1, Bulat Faezov2,3, Kishan R Patel1

  • 1Fels Cancer Institute for Personalized Medicine. Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.

Nature Communications
|July 9, 2024
PubMed

Insights

FAM122A acts as a competitive inhibitor of protein phosphatase 2A (PP2A) by blocking substrate binding. This protein regulates cell cycle progression and DNA damage response.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Protein phosphatase 2A (PP2A) is crucial for dephosphorylating phosphoproteins.
  • B regulatory subunits mediate substrate recognition for PP2A.
  • FAM122A is identified as an inhibitor of B55α/PP2A.

Purpose of the Study:

  • To identify and characterize the mechanism of FAM122A as a PP2A inhibitor.
  • To investigate the role of FAM122A in cell cycle regulation and DNA damage response.

Main Methods:

  • Identification of a conserved substrate motif in FAM122A.
  • Computational structure prediction of FAM122A-B55α interaction.
  • In vitro assays using cell lysates to assess enzyme inhibition.
  • Analysis of FAM122A-deficient cell lines and knockout models (HEK293).

Main Results:

  • A conserved motif [RK]-V-x-x-[VI]-R in FAM122A is essential for B55α binding.
  • FAM122A acts as a competitive inhibitor, preventing substrate binding and dephosphorylation of CDK substrates by B55α/PP2A.
  • FAM122A deficiency impairs cell proliferation, cell cycle progression (G1/S and intra-S), and attenuates CHK1/CHK2 activation during replication stress.

Conclusions:

  • FAM122A is a short helical motif (SHeM)-dependent inhibitor of B55α/PP2A.
  • FAM122A competitively inhibits PP2A by blocking substrate docking.
  • FAM122A plays a significant role in suppressing B55α functions in DNA damage response and cell cycle progression.

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