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J. Biol. Chem., Vol. 278, Issue 6, 4295-4304, February 7, 2003
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From the Department of Cancer Genetics, Roswell Park Cancer
Institute, Buffalo, New York 14263
DNA replication is inhibited by DNA damage
through cis effects on replication fork progression and
trans effects associated with checkpoints. In this study,
we employed a combined pulse labeling and neutral-neutral
two-dimensional gel-based approach to compare the effects of a DNA
damaging agent frequently employed to invoke checkpoints, UVC
radiation, on the replication of cellular and simian virus 40 (SV40)
chromosomes in intact cells. UVC radiation induced similar inhibitory
effects on the initiation and elongation phases of cellular and SV40
DNA replication. The initiation-inhibitory effects occurred
independently of p53 and were abrogated by the ATM and ATR kinase
inhibitor caffeine, or the Chk1 kinase inhibitor UCN-01. Inhibition of
cellular origins was also abrogated by the expression of a
dominant-negative Chk1 mutant. These results indicate that UVC induces
a Chk1- and ATR or ATM-dependent checkpoint that targets
both cellular and SV40 viral replication origins. Loss of Chk1 and ATR
or ATM function also stimulated initiation of cellular and viral DNA
replication in the absence of UVC radiation, revealing the existence of
a novel intrinsic checkpoint that targets both cellular and SV40 viral
origins of replication in the absence of DNA damage or stalled DNA
replication forks. This checkpoint inhibits the replication in early S
phase cells of a region of the repetitive rDNA locus that replicates in
late S phase. The ability to detect these checkpoints using the well
characterized SV40 model system should facilitate analysis of the
molecular basis for these effects.
Regulation of Cellular and SV40 Virus Origins of Replication
by Chk1-dependent Intrinsic and UVC Radiation-induced
Checkpoints*
§,
*
This work was supported by National Science Foundation Grant
MCB 9317011, United States Public Health Service Grant CA 84086, and by
shared resources funded by Roswell Park Cancer Center Support Grant P30
CA16056.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.
Current address: Human Genome Sciences, Inc., 9410 Key West Ave.,
Rockville, MD 20850.
§
Both authors contributed equally to the results of this work.
¶
To whom correspondence should be addressed. Tel.:
716-845-7691; Fax: 716-845-1579; E-mail:
wburhans@acsu.buffalo.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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