A novel DNA damage checkpoint involving post-transcriptional regulation of cyclin A expression.
The intracellular metabolism of many carcinogenic polycyclic aryl hydrocarbons (PAHs, typified by the ubiquitous pollutant benzo[a]pyrene or B[a]P) generates electrophilic products that react covalently with genomic DNA. Cells that acquire PAH-induced DNA damage undergo growth arrest in a p53-independent manner (Vaziri, C., and Faller, D. V. (1997) J. Biol. Chem. 272, 2762-2769). In this report we have investigated the molecular basis of PAH-induced cell cycle arrest. Mitogenic signaling events involving cyclins D and E, Rb phosphorylation, and transcriptional activation of E2F-responsive genes (including cyclin E and cyclin A) were unaffected in cells containing PAH-damaged DNA. However, PAH-induced growth arrest was associated with post-transcriptional decreases in cyclin A expression. Mitogen-induced expression of cyclin B, an event that is temporally distal to cyclin A expression, was also inhibited in PAH-treated cells. The PAH-induced cell cycle block was transient, and arrested cells resumed DNA synthesis after a prolonged ( approximately 20 h) delay. Resumption of DNA synthesis in PAH-treated cells occurred concomitant with elevated expression of cyclins A and B. PAH-induced cell cycle arrest was overcome by ectopically expressed cyclin A (encoded by a recombinant adenovirus in transiently infected cells). Overall, our results suggest the existence of a DNA damage checkpoint pathway that arrests cell cycle progression via post-transcriptional control of cyclin A expression.
Guo
N
N
Cancer Research Center, Boston University School of Medicine, Boston Massachusetts 02118, USA.
Faller
D V
DV
Vaziri
C
C
D016475:3T3 Cells; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D002352:Carrier Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D015151:Immunoblotting; D051379:Mice; D008934:Mitogens / Q000378:metabolism; D009153:Mutagens / Q000633:toxicity; D011083:Polycyclic Compounds / Q000633:toxicity; D012323:RNA Processing, Post-Transcriptional; D016160:Retinoblastoma Protein / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D015398:Signal Transduction / Q000187:drug effects; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019925:Cyclin A; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D008934:Mitogens; D009153:Mutagens; D011083:Polycyclic Compounds; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D019938:Cyclin D1; D001564:Benzo(a)pyrene