Distinct phosphatases antagonize the p53 response in different phases of the cell cycle

Indra A. Shaltiel, Melinda Aprelia, Adrian T. Saurin, Dipanjan Chowdhury, Geert J. P. L. Kops, Emile E. Voest, Rene H. Medema (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    48 Citations (Scopus)
    114 Downloads (Pure)

    Abstract

    The basic machinery that detects DNA damage is the same throughout the cell cycle. Here, we show, in contrast, that reversal of DNA damage responses (DDRs) and recovery are fundamentally different in G1 and G2 phases of the cell cycle. We find that distinct phosphatases are required to counteract the checkpoint response in G1 vs. G2. Whereas WT p53-induced phosphatase 1 (Wip1) promotes recovery in G2-Arrested cells by antagonizing p53, it is dispensable for recovery from a G1 arrest. Instead, we identify phosphoprotein phosphatase 4 catalytic subunit (PP4) to be specifically required for cell cycle restart after DNA damage in G1. PP4 dephosphorylates Krüppel-Associated box domain-Associated protein 1-S473 to repress p53-dependent transcriptional activation of p21 when the DDR is silenced. Taken together, our results show that PP4 and Wip1 are differentially required to counteract the p53-dependent cell cycle arrest in G1 and G2, by antagonizing early or late p53-mediated responses, respectively.
    Original languageEnglish
    Pages (from-to)7313-7318
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume111
    Issue number20
    Early online date7 Apr 2014
    DOIs
    Publication statusPublished - 20 May 2014

    Keywords

    • Cell Cycle
    • Checkpoint Kinase 2
    • Cyclin B1
    • DNA
    • DNA Damage
    • Fibroblasts
    • G1 Phase
    • G2 Phase
    • Gene Expression Regulation, Neoplastic
    • Humans
    • Luminescent Proteins
    • Mutation
    • Phosphoprotein Phosphatases
    • Phosphorylation
    • Protein Structure, Tertiary
    • Retinal Pigment Epithelium
    • Telomerase
    • Tumor Suppressor Protein p53
    • p38 Mitogen-Activated Protein Kinases

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