The human decatenation checkpoint

PB Deming, CA Cistulli, H Zhao, PR Graves, H Piwnica-Worms, RS Paules, Stephen Downes, WK Kaufmann

    Research output: Contribution to journalArticle

    142 Citations (Scopus)

    Abstract

    Chromatid catenation is actively monitored in human cells, with progression from G(2) to mitosis being inhibited when chromatids are insufficiently decatenated. Mitotic delay was quantified in normal and checkpoint-deficient human cells during treatment with ICRF-193, a topoisomerase II catalytic inhibitor that prevents chromatid decatenation without producing topoisomerase-associated DNA strand breaks. Ataxia telangiectasia (A-T) cells, defective in DNA damage checkpoints, showed normal mitotic delay when treated with ICRF-193. The mitotic delay in response to ICRF-193 was ablated in human fibroblasts expressing an ataxia telangiectasia mutated- and rad3-related (ATR) kinase-inactive ATR allele (ATR(ki)). BRCA1-mutant HCC1937 cells also displayed a defect in ICRF-193-induced mitotic delay, which was corrected by expression of wild-type BRCA1. Phosphorylations of hCds1 or Chk1 and inhibition of Cdk1 kinase activity, which are elements of checkpoints associated with DNA damage or replication, did not occur during ICRF-193-induced mitotic delay. Over-expression of cyclin B1 containing a dominant nuclear localization signal, and inhibition of Crm1-mediated nuclear export, reversed ICRF-193-induced mitotic delay. In combination, these results imply that ATR and BRCA1 enforce the decatenation G(2) checkpoint, which may act to exclude cyclin B1/Cdk1 complexes from the nucleus. Moreover, induction of ATR(ki) produced a 10-fold increase in chromosomal aberrations, further emphasizing the vital role for ATR in genetic stability.
    LanguageEnglish
    Pages12044-12049
    JournalPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    Volume98
    Issue number21
    Publication statusPublished - Oct 2001

    Fingerprint

    Ataxia Telangiectasia
    Chromatids
    Cyclin B1
    DNA Damage
    CDC2 Protein Kinase
    Topoisomerase II Inhibitors
    Nuclear Localization Signals
    DNA Breaks
    Cell Nucleus Active Transport
    DNA Replication
    Mitosis
    Chromosome Aberrations
    4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione
    Phosphotransferases
    Fibroblasts
    Alleles
    Phosphorylation

    Cite this

    Deming, PB., Cistulli, CA., Zhao, H., Graves, PR., Piwnica-Worms, H., Paules, RS., ... Kaufmann, WK. (2001). The human decatenation checkpoint. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 98(21), 12044-12049.
    Deming, PB ; Cistulli, CA ; Zhao, H ; Graves, PR ; Piwnica-Worms, H ; Paules, RS ; Downes, Stephen ; Kaufmann, WK. / The human decatenation checkpoint. In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2001 ; Vol. 98, No. 21. pp. 12044-12049.
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    Deming, PB, Cistulli, CA, Zhao, H, Graves, PR, Piwnica-Worms, H, Paules, RS, Downes, S & Kaufmann, WK 2001, 'The human decatenation checkpoint', PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 98, no. 21, pp. 12044-12049.

    The human decatenation checkpoint. / Deming, PB; Cistulli, CA; Zhao, H; Graves, PR; Piwnica-Worms, H; Paules, RS; Downes, Stephen; Kaufmann, WK.

    In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol. 98, No. 21, 10.2001, p. 12044-12049.

    Research output: Contribution to journalArticle

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    AU - Deming, PB

    AU - Cistulli, CA

    AU - Zhao, H

    AU - Graves, PR

    AU - Piwnica-Worms, H

    AU - Paules, RS

    AU - Downes, Stephen

    AU - Kaufmann, WK

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    N2 - Chromatid catenation is actively monitored in human cells, with progression from G(2) to mitosis being inhibited when chromatids are insufficiently decatenated. Mitotic delay was quantified in normal and checkpoint-deficient human cells during treatment with ICRF-193, a topoisomerase II catalytic inhibitor that prevents chromatid decatenation without producing topoisomerase-associated DNA strand breaks. Ataxia telangiectasia (A-T) cells, defective in DNA damage checkpoints, showed normal mitotic delay when treated with ICRF-193. The mitotic delay in response to ICRF-193 was ablated in human fibroblasts expressing an ataxia telangiectasia mutated- and rad3-related (ATR) kinase-inactive ATR allele (ATR(ki)). BRCA1-mutant HCC1937 cells also displayed a defect in ICRF-193-induced mitotic delay, which was corrected by expression of wild-type BRCA1. Phosphorylations of hCds1 or Chk1 and inhibition of Cdk1 kinase activity, which are elements of checkpoints associated with DNA damage or replication, did not occur during ICRF-193-induced mitotic delay. Over-expression of cyclin B1 containing a dominant nuclear localization signal, and inhibition of Crm1-mediated nuclear export, reversed ICRF-193-induced mitotic delay. In combination, these results imply that ATR and BRCA1 enforce the decatenation G(2) checkpoint, which may act to exclude cyclin B1/Cdk1 complexes from the nucleus. Moreover, induction of ATR(ki) produced a 10-fold increase in chromosomal aberrations, further emphasizing the vital role for ATR in genetic stability.

    AB - Chromatid catenation is actively monitored in human cells, with progression from G(2) to mitosis being inhibited when chromatids are insufficiently decatenated. Mitotic delay was quantified in normal and checkpoint-deficient human cells during treatment with ICRF-193, a topoisomerase II catalytic inhibitor that prevents chromatid decatenation without producing topoisomerase-associated DNA strand breaks. Ataxia telangiectasia (A-T) cells, defective in DNA damage checkpoints, showed normal mitotic delay when treated with ICRF-193. The mitotic delay in response to ICRF-193 was ablated in human fibroblasts expressing an ataxia telangiectasia mutated- and rad3-related (ATR) kinase-inactive ATR allele (ATR(ki)). BRCA1-mutant HCC1937 cells also displayed a defect in ICRF-193-induced mitotic delay, which was corrected by expression of wild-type BRCA1. Phosphorylations of hCds1 or Chk1 and inhibition of Cdk1 kinase activity, which are elements of checkpoints associated with DNA damage or replication, did not occur during ICRF-193-induced mitotic delay. Over-expression of cyclin B1 containing a dominant nuclear localization signal, and inhibition of Crm1-mediated nuclear export, reversed ICRF-193-induced mitotic delay. In combination, these results imply that ATR and BRCA1 enforce the decatenation G(2) checkpoint, which may act to exclude cyclin B1/Cdk1 complexes from the nucleus. Moreover, induction of ATR(ki) produced a 10-fold increase in chromosomal aberrations, further emphasizing the vital role for ATR in genetic stability.

    M3 - Article

    VL - 98

    SP - 12044

    EP - 12049

    JO - Proceedings of the National Academy of Sciences

    T2 - Proceedings of the National Academy of Sciences

    JF - Proceedings of the National Academy of Sciences

    SN - 0027-8424

    IS - 21

    ER -

    Deming PB, Cistulli CA, Zhao H, Graves PR, Piwnica-Worms H, Paules RS et al. The human decatenation checkpoint. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2001 Oct;98(21):12044-12049.