ATR enforces the topoisomerase II-dependent G(2) checkpoint through inhibition of Plk1 kinase

PB Deming, KG Flores, Stephen Downes, RS Paules, WK Kaufmann

    Research output: Contribution to journalArticle

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    Abstract

    An ATR-dependent G(2) checkpoint responds to inhibition of topoisomerase 11 and delays entry into mitosis by sustaining nuclear exclusion of cyclin B1-Cdk1 complexes. Here we report that induction of this checkpoint with ICRF-193, a topoisomerase H catalytic inhibitor that does not cause DNA damage, was associated with an ATR-dependent inhibition of polo-like kinase 1 (Plk1) kinase activity and a decrease in cyclin B1 phosphorylation. Expression of constitutively active Plk1 but not wild type Plk1 reversed ICRF-193-induced mitotic delay in HeLa cells, suggesting that Plk1 kinase activity is important for the checkpoint response to ICRF-193. G(2)/M synchronized normal human fibroblasts, when treated with ICRF-193, showed a decrease in cyclin B1 phosphorylation and Plk1 kinase activity despite high cyclin B1-Cdk1 kinase activity. G(2) fibroblasts that were treated with caffeine to override the checkpoint response to ICRF-193 displayed a high incidence of chromosomal aberrations. Taken together, these results suggest that ATR-dependent inhibition of Plk1 kinase activity may be one mechanism to regulate cyclin B1 phosphorylation and sustain nuclear exclusion during the G(2) checkpoint response to topoisomerase 11 inhibition. Moreover, the results demonstrate an important role for the topoisomerase II-dependent G(2) checkpoint in the preservation of human genomic stability.
    LanguageEnglish
    Pages36832-36838
    JournalJournal of Biological Chemistry
    Volume277
    Issue number39
    DOIs
    Publication statusPublished - Sep 2002

    Fingerprint

    Type II DNA Topoisomerase
    Cyclin B1
    Phosphotransferases
    Phosphorylation
    Fibroblasts
    CDC2 Protein Kinase
    Genomic Instability
    Caffeine
    HeLa Cells
    Mitosis
    Chromosome Aberrations
    DNA Damage
    polo-like kinase 1
    4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione
    Incidence

    Cite this

    Deming, PB ; Flores, KG ; Downes, Stephen ; Paules, RS ; Kaufmann, WK. / ATR enforces the topoisomerase II-dependent G(2) checkpoint through inhibition of Plk1 kinase. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 39. pp. 36832-36838.
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    abstract = "An ATR-dependent G(2) checkpoint responds to inhibition of topoisomerase 11 and delays entry into mitosis by sustaining nuclear exclusion of cyclin B1-Cdk1 complexes. Here we report that induction of this checkpoint with ICRF-193, a topoisomerase H catalytic inhibitor that does not cause DNA damage, was associated with an ATR-dependent inhibition of polo-like kinase 1 (Plk1) kinase activity and a decrease in cyclin B1 phosphorylation. Expression of constitutively active Plk1 but not wild type Plk1 reversed ICRF-193-induced mitotic delay in HeLa cells, suggesting that Plk1 kinase activity is important for the checkpoint response to ICRF-193. G(2)/M synchronized normal human fibroblasts, when treated with ICRF-193, showed a decrease in cyclin B1 phosphorylation and Plk1 kinase activity despite high cyclin B1-Cdk1 kinase activity. G(2) fibroblasts that were treated with caffeine to override the checkpoint response to ICRF-193 displayed a high incidence of chromosomal aberrations. Taken together, these results suggest that ATR-dependent inhibition of Plk1 kinase activity may be one mechanism to regulate cyclin B1 phosphorylation and sustain nuclear exclusion during the G(2) checkpoint response to topoisomerase 11 inhibition. Moreover, the results demonstrate an important role for the topoisomerase II-dependent G(2) checkpoint in the preservation of human genomic stability.",
    author = "PB Deming and KG Flores and Stephen Downes and RS Paules and WK Kaufmann",
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    Deming, PB, Flores, KG, Downes, S, Paules, RS & Kaufmann, WK 2002, 'ATR enforces the topoisomerase II-dependent G(2) checkpoint through inhibition of Plk1 kinase', Journal of Biological Chemistry, vol. 277, no. 39, pp. 36832-36838. https://doi.org/10.1074/jbc.M206109200

    ATR enforces the topoisomerase II-dependent G(2) checkpoint through inhibition of Plk1 kinase. / Deming, PB; Flores, KG; Downes, Stephen; Paules, RS; Kaufmann, WK.

    In: Journal of Biological Chemistry, Vol. 277, No. 39, 09.2002, p. 36832-36838.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - ATR enforces the topoisomerase II-dependent G(2) checkpoint through inhibition of Plk1 kinase

    AU - Deming, PB

    AU - Flores, KG

    AU - Downes, Stephen

    AU - Paules, RS

    AU - Kaufmann, WK

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    N2 - An ATR-dependent G(2) checkpoint responds to inhibition of topoisomerase 11 and delays entry into mitosis by sustaining nuclear exclusion of cyclin B1-Cdk1 complexes. Here we report that induction of this checkpoint with ICRF-193, a topoisomerase H catalytic inhibitor that does not cause DNA damage, was associated with an ATR-dependent inhibition of polo-like kinase 1 (Plk1) kinase activity and a decrease in cyclin B1 phosphorylation. Expression of constitutively active Plk1 but not wild type Plk1 reversed ICRF-193-induced mitotic delay in HeLa cells, suggesting that Plk1 kinase activity is important for the checkpoint response to ICRF-193. G(2)/M synchronized normal human fibroblasts, when treated with ICRF-193, showed a decrease in cyclin B1 phosphorylation and Plk1 kinase activity despite high cyclin B1-Cdk1 kinase activity. G(2) fibroblasts that were treated with caffeine to override the checkpoint response to ICRF-193 displayed a high incidence of chromosomal aberrations. Taken together, these results suggest that ATR-dependent inhibition of Plk1 kinase activity may be one mechanism to regulate cyclin B1 phosphorylation and sustain nuclear exclusion during the G(2) checkpoint response to topoisomerase 11 inhibition. Moreover, the results demonstrate an important role for the topoisomerase II-dependent G(2) checkpoint in the preservation of human genomic stability.

    AB - An ATR-dependent G(2) checkpoint responds to inhibition of topoisomerase 11 and delays entry into mitosis by sustaining nuclear exclusion of cyclin B1-Cdk1 complexes. Here we report that induction of this checkpoint with ICRF-193, a topoisomerase H catalytic inhibitor that does not cause DNA damage, was associated with an ATR-dependent inhibition of polo-like kinase 1 (Plk1) kinase activity and a decrease in cyclin B1 phosphorylation. Expression of constitutively active Plk1 but not wild type Plk1 reversed ICRF-193-induced mitotic delay in HeLa cells, suggesting that Plk1 kinase activity is important for the checkpoint response to ICRF-193. G(2)/M synchronized normal human fibroblasts, when treated with ICRF-193, showed a decrease in cyclin B1 phosphorylation and Plk1 kinase activity despite high cyclin B1-Cdk1 kinase activity. G(2) fibroblasts that were treated with caffeine to override the checkpoint response to ICRF-193 displayed a high incidence of chromosomal aberrations. Taken together, these results suggest that ATR-dependent inhibition of Plk1 kinase activity may be one mechanism to regulate cyclin B1 phosphorylation and sustain nuclear exclusion during the G(2) checkpoint response to topoisomerase 11 inhibition. Moreover, the results demonstrate an important role for the topoisomerase II-dependent G(2) checkpoint in the preservation of human genomic stability.

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