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

Author:

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

Abstract

AbstractThe 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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

Division of Cancer Prevention, National Cancer Institute

U.S. Department of Health & Human Services | NIH | National Cancer Institute

WW Smith Charitable Trust Award

Publisher

Springer Science and Business Media LLC

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