Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin/cdk2 activity.
DNA and histone synthesis are both triggered at the beginning of S phase by cyclin/cdk2 activity. Previous studies showed that inhibition of DNA synthesis with hydroxyurea or cytosine arabinoside (AraC) triggers a concerted repression of histone synthesis, indicating that sustained histone synthesis depends on continued DNA synthesis. Here we show that ectopic expression of HIRA, the likely human ortholog of two cell cycle-regulated repressors of histone gene transcription in yeast (Hir1p and Hir2p), represses transcription of histones and that this, in turn, triggers a concerted block of DNA synthesis. Thus, in mammalian cells sustained DNA synthesis and histone synthesis are mutually dependent on each other during S phase. Although cyclin/cdk2 activity drives activation of both DNA and histone synthesis at the G1/S transition of cycling cells, concerted repression of DNA or histone synthesis in response to inhibition of either one of these is not accompanied by prolonged inhibition of cyclin A/cdk2 or E/cdk2 activity. Therefore, during S phase coupling of DNA and histone synthesis occurs, at least in part, through a mechanism that is independent of cyclin/cdk2 activity. Coupling of DNA and histone synthesis in S phase presumably contributes to the prompt and orderly assembly of newly replicated DNA into chromatin.
Nelson
David M
DM
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Ye
Xiaofen
X
Hall
Caitlin
C
Santos
Hidelita
H
Ma
Tianlin
T
Kao
Gary D
GD
Yen
Timothy J
TJ
Harper
J Wade
JW
Adams
Peter D
PD
D018941:Antigens, CD19 / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis*; D003609:Dactinomycin / Q000494:pharmacology; D005434:Flow Cytometry; D005656:Fungal Proteins / Q000378:metabolism; D006657:Histones / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D008836:Micrococcal Nuclease / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D016196:S Phase; D029701:Saccharomyces cerevisiae Proteins; D013997:Time Factors; D014162:Transfection
D018941:Antigens, CD19; D002843:Chromatin; D019925:Cyclin A; D005656:Fungal Proteins; C078808:HIR1 protein, S cerevisiae; C078809:HIR2 protein, S cerevisiae; D006657:Histones; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D003609:Dactinomycin; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D008836:Micrococcal Nuclease