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J Biol Chem, Vol. 275, Issue 3, 1715-1722, January 21, 2000
From the Cancer Research Center, Boston University School of
Medicine, Boston Massachusetts 02118
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 (~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.
A Novel DNA Damage Checkpoint Involving Post-transcriptional
Regulation of Cyclin A Expression*
*
This work was funded by American Cancer Society Grant
IRG-72-001-24-IRG, a grant from the American Cancer Society,
Massachusetts Division, Inc., and National Institutes of Health Grants
ES09558 (to C. V.) and CA50454 (to D. V. F.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Cancer Research
Center, Boston University School of Medicine, 80 E. Concord St., Boston
MA 02118. Tel.: 617-638-4175; Fax: 617-638-5609; E-mail: cvaziri@acs.bu.edu.
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