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 PAM-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 PAM-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 PAM-damaged DNA. However, PAM-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 PAM-treated cells. The PAM-induced cell cycle block was transient, and arrested cells resumed DNA synthesis after a prolonged (similar to 20 h) delay. Resumption of DNA synthesis in PAM-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.