Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 22, Issue 21, Pages 7459-7472Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.22.21.7459-7472.2002
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Funding
- NCI NIH HHS [P01 CA075138, CA75138] Funding Source: Medline
- NIGMS NIH HHS [R01 GM054137, R01 GM062281, R01-GM62281, GM54137, R01 GM044762, GM44762] Funding Source: Medline
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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 G(1)/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.
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