title: Nuclear reorganization of mammalian DNA synthesis prior to cell cycle exit.
abstract: 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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kudlow
authors.forename: Richard
authors.initials: R
authors.lastname: Frock
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhao
authors.forename: Brett R
authors.initials: BR
authors.lastname: Johnson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Dyson
authors.forename: Ed
authors.initials: E
authors.lastname: Harlow
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
mesh_terms: D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis*; D004258:DNA Polymerase III / Q000378:metabolism; D004261:DNA Replication; D006657:Histones / Q000235:genetics; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016196:S Phase
chemical_list: D002843:Chromatin; D006657:Histones; D018809:Proliferating Cell Nuclear Antigen; D004247:DNA; D004258:DNA Polymerase III