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© The Rockefeller University Press, 0021-9525/1998//1013 $5.00
The Journal of Cell Biology, Volume 142, Number 4, , 1998 1013-1022

Articles

Entry into Mitosis in Vertebrate Somatic Cells Is Guarded by a Chromosome Damage Checkpoint That Reverses the Cell Cycle When Triggered during Early but Not Late Prophase



Conly L. Rieder*,{ddagger} and Richard W. Cole*

* Division of Molecular Medicine, Wadsworth Center, New York State Department of Health, Albany, New York 12201-0509; and {ddagger} Department of Biomedical Sciences, State University of New York, Albany, New York 12222

When vertebrate somatic cells are selectively irradiated in the nucleus during late prophase (<30 min before nuclear envelope breakdown) they progress normally through mitosis even if they contain broken chromosomes. However, if early prophase nuclei are similarly irradiated, chromosome condensation is reversed and the cells return to interphase. Thus, the G2 checkpoint that prevents entry into mitosis in response to nuclear damage ceases to function in late prophase. If one nucleus in a cell containing two early prophase nuclei is selectively irradiated, both return to interphase, and prophase cells that have been induced to returned to interphase retain a normal cytoplasmic microtubule complex. Thus, damage to an early prophase nucleus is converted into a signal that not only reverses the nuclear events of prophase, but this signal also enters the cytoplasm where it inhibits e.g., centrosome maturation and the formation of asters. Immunofluorescent analyses reveal that the irradiation-induced reversion of prophase is correlated with the dephosphorylation of histone H1, histone H3, and the MPM2 epitopes. Together, these data reveal that a checkpoint control exists in early but not late prophase in vertebrate cells that, when triggered, reverses the cell cycle by apparently downregulating existing cyclin-dependent kinase (CDK1) activity.

Key Words: checkpoint control • G2/M transition • CDK1 • mitosis • radiation

Abbreviations used in this paper: CDK1, cyclin-dependent kinase 1; DIC, differential interference contrast; IMF, immunofluorescent; LM, light microscopy; M–A, metaphase–anaphase; Mts, microtubules; NEB, nuclear envelope breakdown.

This work was supported, in part, by a grant from the National Institutes of Health (NIH) General Medical Sciences (R01 40198) to C.L. Rieder, and by a grant from NIH/National Center for Research Resources (P4101219) which supports the Wadsworth Center's Biological Microscopy and Image Reconstruction facility as a National Biotechnological Resource.

Address all correspondence to Conly L. Rieder, Division of Molecular Medicine, Wadsworth Center, P.O. Box 509, Albany, New York 12201-0509. Tel.: (518) 474-6774. Fax: (518) 486-4901. E-mail: rieder{at}wadsworth.org


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