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Molecular and Cellular Biology, January 2004, p. 595-607, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.595-607.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Nuclear Reorganization of Mammalian DNA Synthesis Prior to Cell Cycle Exit

David A. Barbie,1 Brian A. Kudlow,2,3 Richard Frock,2 Jiyong Zhao,1,4 Brett R. Johnson,1 Nicholas Dyson,1 Ed Harlow,1,5 and Brian K. Kennedy1,2*

Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129,1 Department of Biochemistry,2 Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 98195,3 Department of Biomedical Genetics, University of Rochester, Rochester, New York 14642,4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 021155

Received 11 August 2003/ Returned for modification 17 September 2003/ Accepted 15 October 2003

In primary mammalian cells, DNA replication initiates in a small number of perinucleolar, lamin A/C-associated foci. During S-phase progression in proliferating cells, replication foci distribute to hundreds of sites throughout the nucleus. In contrast, we find that the limited perinucleolar replication sites persist throughout S phase as cells prepare to exit the cell cycle in response to contact inhibition, serum starvation, or replicative senescence. Proteins known to be involved in DNA synthesis, such as PCNA and DNA polymerase {delta}, are concentrated in perinucleolar foci throughout S phase under these conditions. Moreover, chromosomal loci are redirected toward the nucleolus and overlap with the perinucleolar replication foci in cells poised to undergo cell cycle exit. These same loci remain in the periphery of the nucleus during replication under highly proliferative conditions. These results suggest that mammalian cells undergo a large-scale reorganization of chromatin during the rounds of DNA replication that precede cell cycle exit.

* Corresponding author. Mailing address: Department of Biochemistry, University of Washington, Seattle, WA 98195. Phone: (206) 685-0111. Fax: (206) 685-1792. E-mail: bkenn{at}u.washington.edu.

Molecular and Cellular Biology, January 2004, p. 595-607, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.595-607.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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