Characterization of the role of a trimeric protein phosphatase complex in recovery from cisplatin-induced versus noncrosslinking DNA damage

Cristina Vazquez-Martin, John Rouse, Patricia T. W. Cohen (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    Abstract

    Cisplatin (cis-diamminedichloroplatinum) and related chemotherapeutic DNA-crosslinking agents are widely used to treat human cancers. Saccharomyces cerevisiae with separate deletions of the genes encoding the trimeric protein serine/threonine phosphatase (Pph)3p-platinum sensitivity (Psy)4p-Psy2p complex, are more sensitive than the isogenic wild-type (WT) strain to cisplatin. We show here that cisplatin causes an enhanced intra-S-phase cell cycle delay in these three deletion mutants. The C-terminal tail of histone 2AX (H2AX) is hyperphosphorylated in the same mutants, and Pph3p is found to interact with phosphorylated H2AX (gamma H2AX). After cisplatin treatment is terminated, pph3 Delta, psy4 Delta and psy2 Delta mutants are delayed as compared with the WT strain in the dephosphorylation of Rad53p. In contrast, only pph3 Delta and psy2 Delta cells are more sensitive than WT cells to methylmethanesulfonate, a noncrosslinking DNA-alkylating agent that is known to cause a Rad53p-dependent intra-S-phase cell cycle delay. Dephosphorylation of Rad53p and the recovery of chromosome replication are delayed in the same mutants, but not in psy4 Delta cells. By comparison with their mammalian orthologues, the regulatory subunit Psy4p is likely to inhibit Pph3p catalytic activity. The presence of a weak but active Pph3p-Psy2p complex may allow psy4 Delta cells to escape from the Rad53p-mediated cell cycle arrest. Overall, our data suggest that the trimeric Pph3p-Psy4p-Psy2p complex may dephosphorylate both gamma H2AX and Rad53p, the differences lying in the more stable interaction of the Pph3 phosphatase with gamma H2AX as opposed to a transient interaction with Rad53p.

    Original languageEnglish
    Pages (from-to)4211-4221
    Number of pages11
    JournalFEBS Journal
    Volume275
    Issue number16
    DOIs
    Publication statusPublished - Aug 2008

    Cite this

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    title = "Characterization of the role of a trimeric protein phosphatase complex in recovery from cisplatin-induced versus noncrosslinking DNA damage",
    abstract = "Cisplatin (cis-diamminedichloroplatinum) and related chemotherapeutic DNA-crosslinking agents are widely used to treat human cancers. Saccharomyces cerevisiae with separate deletions of the genes encoding the trimeric protein serine/threonine phosphatase (Pph)3p-platinum sensitivity (Psy)4p-Psy2p complex, are more sensitive than the isogenic wild-type (WT) strain to cisplatin. We show here that cisplatin causes an enhanced intra-S-phase cell cycle delay in these three deletion mutants. The C-terminal tail of histone 2AX (H2AX) is hyperphosphorylated in the same mutants, and Pph3p is found to interact with phosphorylated H2AX (gamma H2AX). After cisplatin treatment is terminated, pph3 Delta, psy4 Delta and psy2 Delta mutants are delayed as compared with the WT strain in the dephosphorylation of Rad53p. In contrast, only pph3 Delta and psy2 Delta cells are more sensitive than WT cells to methylmethanesulfonate, a noncrosslinking DNA-alkylating agent that is known to cause a Rad53p-dependent intra-S-phase cell cycle delay. Dephosphorylation of Rad53p and the recovery of chromosome replication are delayed in the same mutants, but not in psy4 Delta cells. By comparison with their mammalian orthologues, the regulatory subunit Psy4p is likely to inhibit Pph3p catalytic activity. The presence of a weak but active Pph3p-Psy2p complex may allow psy4 Delta cells to escape from the Rad53p-mediated cell cycle arrest. Overall, our data suggest that the trimeric Pph3p-Psy4p-Psy2p complex may dephosphorylate both gamma H2AX and Rad53p, the differences lying in the more stable interaction of the Pph3 phosphatase with gamma H2AX as opposed to a transient interaction with Rad53p.",
    author = "Cristina Vazquez-Martin and John Rouse and Cohen, {Patricia T. W.}",
    year = "2008",
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    language = "English",
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    Characterization of the role of a trimeric protein phosphatase complex in recovery from cisplatin-induced versus noncrosslinking DNA damage. / Vazquez-Martin, Cristina; Rouse, John; Cohen, Patricia T. W. (Lead / Corresponding author).

    In: FEBS Journal, Vol. 275, No. 16, 08.2008, p. 4211-4221.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Characterization of the role of a trimeric protein phosphatase complex in recovery from cisplatin-induced versus noncrosslinking DNA damage

    AU - Vazquez-Martin, Cristina

    AU - Rouse, John

    AU - Cohen, Patricia T. W.

    PY - 2008/8

    Y1 - 2008/8

    N2 - Cisplatin (cis-diamminedichloroplatinum) and related chemotherapeutic DNA-crosslinking agents are widely used to treat human cancers. Saccharomyces cerevisiae with separate deletions of the genes encoding the trimeric protein serine/threonine phosphatase (Pph)3p-platinum sensitivity (Psy)4p-Psy2p complex, are more sensitive than the isogenic wild-type (WT) strain to cisplatin. We show here that cisplatin causes an enhanced intra-S-phase cell cycle delay in these three deletion mutants. The C-terminal tail of histone 2AX (H2AX) is hyperphosphorylated in the same mutants, and Pph3p is found to interact with phosphorylated H2AX (gamma H2AX). After cisplatin treatment is terminated, pph3 Delta, psy4 Delta and psy2 Delta mutants are delayed as compared with the WT strain in the dephosphorylation of Rad53p. In contrast, only pph3 Delta and psy2 Delta cells are more sensitive than WT cells to methylmethanesulfonate, a noncrosslinking DNA-alkylating agent that is known to cause a Rad53p-dependent intra-S-phase cell cycle delay. Dephosphorylation of Rad53p and the recovery of chromosome replication are delayed in the same mutants, but not in psy4 Delta cells. By comparison with their mammalian orthologues, the regulatory subunit Psy4p is likely to inhibit Pph3p catalytic activity. The presence of a weak but active Pph3p-Psy2p complex may allow psy4 Delta cells to escape from the Rad53p-mediated cell cycle arrest. Overall, our data suggest that the trimeric Pph3p-Psy4p-Psy2p complex may dephosphorylate both gamma H2AX and Rad53p, the differences lying in the more stable interaction of the Pph3 phosphatase with gamma H2AX as opposed to a transient interaction with Rad53p.

    AB - Cisplatin (cis-diamminedichloroplatinum) and related chemotherapeutic DNA-crosslinking agents are widely used to treat human cancers. Saccharomyces cerevisiae with separate deletions of the genes encoding the trimeric protein serine/threonine phosphatase (Pph)3p-platinum sensitivity (Psy)4p-Psy2p complex, are more sensitive than the isogenic wild-type (WT) strain to cisplatin. We show here that cisplatin causes an enhanced intra-S-phase cell cycle delay in these three deletion mutants. The C-terminal tail of histone 2AX (H2AX) is hyperphosphorylated in the same mutants, and Pph3p is found to interact with phosphorylated H2AX (gamma H2AX). After cisplatin treatment is terminated, pph3 Delta, psy4 Delta and psy2 Delta mutants are delayed as compared with the WT strain in the dephosphorylation of Rad53p. In contrast, only pph3 Delta and psy2 Delta cells are more sensitive than WT cells to methylmethanesulfonate, a noncrosslinking DNA-alkylating agent that is known to cause a Rad53p-dependent intra-S-phase cell cycle delay. Dephosphorylation of Rad53p and the recovery of chromosome replication are delayed in the same mutants, but not in psy4 Delta cells. By comparison with their mammalian orthologues, the regulatory subunit Psy4p is likely to inhibit Pph3p catalytic activity. The presence of a weak but active Pph3p-Psy2p complex may allow psy4 Delta cells to escape from the Rad53p-mediated cell cycle arrest. Overall, our data suggest that the trimeric Pph3p-Psy4p-Psy2p complex may dephosphorylate both gamma H2AX and Rad53p, the differences lying in the more stable interaction of the Pph3 phosphatase with gamma H2AX as opposed to a transient interaction with Rad53p.

    U2 - 10.1111/j.1742-4658.2008.06568.x

    DO - 10.1111/j.1742-4658.2008.06568.x

    M3 - Article

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    JF - FEBS Journal

    SN - 1742-464X

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    ER -