| 2016 |
FAM122A directly interacts with PP2A-Aα and B55α subunits (but not B56α) and inhibits the phosphatase activity of the PP2A-Aα/B55α/Cα holoenzyme; additionally, FAM122A promotes poly-ubiquitination and proteasomal degradation of the catalytic subunit PP2A-Cα. |
Co-immunoprecipitation, phosphatase activity assay, ubiquitination assay, overexpression and knockdown in cell lines |
Oncotarget |
Medium |
27588481
|
| 2018 |
FAM122A is SUMOylated at lysine 89, a modification that can be removed by the SUMO protease SENP1; SUMOylation of FAM122A reduces PP2A-Cα protein levels and PP2A phosphatase activity, thereby suppressing cell proliferation. |
Site-directed mutagenesis (K89 mutation), Co-IP/SUMO conjugation assay, SENP1 de-conjugation assay, phosphatase activity assay |
Biochemical and biophysical research communications |
Medium |
29678583
|
| 2020 |
CHK1 directly phosphorylates FAM122A; loss of FAM122A (CRISPR KO) activates PP2A-B55α, which dephosphorylates WEE1 and rescues it from ubiquitin-mediated degradation, elevating WEE1 protein and thereby reducing replication stress and conferring resistance to CHK1 inhibitors. |
CRISPR knockout, in vitro kinase assay (CHK1 phosphorylation of FAM122A), immunoblot for WEE1 ubiquitination and protein level, PP2A activity assay, genetic rescue experiments |
Molecular cell |
High |
33108758
|
| 2020 |
FAM122A directly interacts with the C-terminal zinc finger domain of GATA1, reducing GATA1 chromatin occupancy on target gene promoters and suppressing GATA1 transcriptional activity, thereby inhibiting erythroid differentiation. |
Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), overexpression in primary human hematopoietic progenitor cells and erythroleukemia cells |
Stem cell reports |
Medium |
32763160
|
| 2020 |
FAM122A interacts with TOP2α (but not TOP2β); FAM122A deletion increases TOP2α protein level and enhances TOP2 poison-induced DNA damage in cancer cells without affecting ROS levels or short-term DNA repair, suggesting FAM122A maintains DNA stability by modulating TOP2α. |
Co-immunoprecipitation, CRISPR KO, γH2AX immunofluorescence/foci, comet assay, ROS measurement |
Experimental cell research |
Medium |
32866497
|
| 2023 |
Cryo-EM structures of PP2A:B55 bound to FAM122A (and separately to phosphorylated ARPP19) reveal that FAM122A, an intrinsically disordered protein, binds PP2A:B55 through multiple distinct sites on the B55 subunit in a manner different from ARPP19; NMR and biochemical data show how substrates and inhibitors are recruited to PP2A:B55. |
Single-particle cryo-EM, NMR spectroscopy, biochemical binding assays |
Nature |
High |
38123684
|
| 2023 |
FAM122A contains a conserved short linear motif (SLiM) [RK]-V-x-x-[VI]-R that forms a short α-helix required for binding to the top groove of B55α; a second adjacent helix occludes the catalytic subunit, making FAM122A a substrate-competitive inhibitor of B55α/PP2A that prevents CDK substrate dephosphorylation; FAM122A deficiency abrogates G1/S and intra-S phase checkpoints and attenuates CHK1/CHK2 activation under replication stress. |
Mutagenesis of SLiM, AlphaFold2 structural prediction, in vitro competition/binding assays, dephosphorylation assays in cell lysates, CRISPR KO in HEK293, flow cytometry cell-cycle analysis |
bioRxivpreprint |
Medium |
36945596
|
| 2024 |
FAM122A uses helical motifs (a substrate-docking SHeM [RK]-V-x-x-[VI]-R helix and an adjacent catalytic-subunit-occluding helix) to act as a substrate-competitive inhibitor of B55α/PP2A; FAM122A deficiency impairs G1/S and intra-S phase checkpoint responses and attenuates CHK1 and CHK2 activation after replication stress. |
Mutagenesis of helical motifs, in vitro competition assay, CDK-substrate dephosphorylation assay in cell lysates, CRISPR KO, flow cytometry, immunoblot for checkpoint kinases |
Nature communications |
High |
38982062
|
| 2024 |
FAM122A-dependent inhibition of PP2A-B55 is the initial mitotic-entry event: FAM122A permits phosphorylation of early mitotic substrates by cyclin A/Cdk, enabling full cyclin B/Cdk1 and Greatwall kinase activation; subsequently, Greatwall-phosphorylated Arpp19/ENSA competes with FAM122A and displaces it from PP2A-B55, taking over phosphatase inhibition for the remainder of mitosis. Loss of the FAM122A orthologue in C. elegans prevents germline stem cells from entering mitosis. |
Xenopus egg extract biochemistry (add-back/depletion), C. elegans RNAi (germline mitotic entry assay), immunoblot for Cdk substrate phosphorylation, Greatwall/ENSA phosphorylation assays |
The EMBO journal |
High |
38378890
|
| 2023 |
FAM122A is required for mesendodermal specification and cardiac differentiation from mouse embryonic stem cells; Fam122a conditional cardiac KO causes embryonic lethality with cardiovascular defects; the differentiation defect is mechanistically linked to dysregulation of histone modifications and Wnt and Hippo signalling pathways through modulation of PP2A activity. |
Conditional KO mice, mouse ESC differentiation assays, PP2A activity assay, histone modification immunoblot, Wnt/Hippo pathway reporter assays |
Stem cells (Dayton, Ohio) |
Medium |
36715298
|
| 2026 |
FAM122A inhibits PP2A-B55 through a bipartite binding mechanism: the N-terminal helices and a novel C-terminal region (residues 150–170) are both required for efficient binding; conserved Ser158 within this C-terminal region is important for PP2A-B55 inhibition in human cells and for stimulation of mitotic entry in Xenopus egg extracts; Ser158 phosphorylation occupancy increases at cell cycle stages requiring PP2A-B55 inhibition. |
Systematic alanine scanning of residues 150–170, phospho-site mutagenesis (Ser158), Co-IP in human cells, Xenopus egg extract mitotic-entry assay, phosphoproteomics/cell-cycle staging |
bioRxivpreprint |
Medium |
41928937
|