DOI: 10.1083/jcb.137.1.183. A Role for Cdk2 Kinase in Negatively Regulating DNA Replication during S Phase of the Cell Cycle

A Role for Cdk2 Kinase in Negatively Regulating DNA Replication during S Phase of the Cell Cycle

10.1083/jcb.137.1.183

Crossref journal-article

Rockefeller University Press

The Journal of Cell Biology (291)

Abstract

Using cell-free extracts made from Xenopus eggs, we show that cdk2-cyclin E and A kinases play an important role in negatively regulating DNA replication. Specifically, we demonstrate that the cdk2 kinase concentration surrounding chromatin in extracts increases 200-fold once the chromatin is assembled into nuclei. Further, we find that if the cdk2–cyclin E or A concentration in egg cytosol is increased 16-fold before the addition of sperm chromatin, the chromatin fails to initiate DNA replication once assembled into nuclei. This demonstrates that cdk2–cyclin E or A can negatively regulate DNA replication. With respect to how this negative regulation occurs, we show that high levels of cdk2–cyclin E do not block the association of the protein complex ORC with sperm chromatin but do prevent association of MCM3, a protein essential for replication. Importantly, we find that MCM3 that is prebound to chromatin does not dissociate when cdk2– cyclin E levels are increased. Taken together our results strongly suggest that during the embryonic cell cycle, the low concentrations of cdk2–cyclin E present in the cytosol after mitosis and before nuclear formation allow proteins essential for potentiating DNA replication to bind to chromatin, and that the high concentration of cdk2–cyclin E within nuclei prevents MCM from reassociating with chromatin after replication. This situation could serve, in part, to limit DNA replication to a single round per cell cycle.

Bibliography

Hua, X. H., Yan, H., & Newport, J. (1997). A Role for Cdk2 Kinase in Negatively Regulating DNA Replication during S Phase of the Cell Cycle. The Journal of Cell Biology, 137(1), 183â192.

Authors 3

Xuequn Helen Hua (first)
Hong Yan (additional)
John Newport (additional)

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Dates

Type	When
Created	23 years ago (July 26, 2002, 12:47 p.m.)
Deposited	2 years ago (July 28, 2023, 7:01 p.m.)
Indexed	2 months, 2 weeks ago (June 10, 2025, 2:44 p.m.)
Issued	28 years, 4 months ago (April 7, 1997)
Published	28 years, 4 months ago (April 7, 1997)
Published Online	28 years, 4 months ago (April 7, 1997)
Published Print	28 years, 4 months ago (April 7, 1997)

Funders 0

None

BibTeX

@article{Hua_1997, title={A Role for Cdk2 Kinase in Negatively Regulating DNA Replication during S Phase of the Cell Cycle}, volume={137}, ISSN={1540-8140}, url={http://dx.doi.org/10.1083/jcb.137.1.183}, DOI={10.1083/jcb.137.1.183}, number={1}, journal={The Journal of Cell Biology}, publisher={Rockefeller University Press}, author={Hua, Xuequn Helen and Yan, Hong and Newport, John}, year={1997}, month=apr, pages={183–192} }

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  "abstract": "<jats:p>Using cell-free extracts made from Xenopus eggs, we show that cdk2-cyclin E and A kinases play an important role in negatively regulating DNA replication. Specifically, we demonstrate that the cdk2 kinase concentration surrounding chromatin in extracts increases 200-fold once the chromatin is assembled into nuclei. Further, we find that if the cdk2\u2013cyclin E or A concentration in egg cytosol is increased 16-fold before the addition of sperm chromatin, the chromatin fails to initiate DNA replication once assembled into nuclei. This demonstrates that cdk2\u2013cyclin E or A can negatively regulate DNA replication. With respect to how this negative regulation occurs, we show that high levels of cdk2\u2013cyclin E do not block the association of the protein complex ORC with sperm chromatin but do prevent association of MCM3, a protein essential for replication. Importantly, we find that MCM3 that is prebound to chromatin does not dissociate when cdk2\u2013 cyclin E levels are increased. Taken together our results strongly suggest that during the embryonic cell cycle, the low concentrations of cdk2\u2013cyclin E present in the cytosol after mitosis and before nuclear formation allow proteins essential for potentiating DNA replication to bind to chromatin, and that the high concentration of cdk2\u2013cyclin E within nuclei prevents MCM from reassociating with chromatin after replication. This situation could serve, in part, to limit DNA replication to a single round per cell cycle.</jats:p>",
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