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J. Biol. Chem., Vol. 276, Issue 23, 20579-20588, June 8, 2001
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From the Department of Radiation Oncology, Division of Experimental
Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College,
Philadelphia, Pennsylvania 19107
Heat shock inhibits replicative DNA synthesis,
but the underlying mechanism remains unknown. We investigated
mechanistic aspects of this regulation in melanoma cells using a simian
virus 40 (SV40)-based in vitro DNA replication assay. Heat
shock (44 °C) caused a monotonic inhibition of cellular DNA
replication following exposures for 5-90 min. SV40 DNA replication
activity in extracts of similarly heated cells also decreased after
5-30 min of exposure, but returned to near control levels after 60-90
min of exposure. This transient inhibition of SV40 DNA replication was
eliminated by recombinant replication protein A (rRPA), suggesting a
regulatory process targeting this key DNA replication factor. SV40 DNA
replication inhibition was associated with a transient increase in the
interaction between nucleolin and RPA that peaked at 20-30 min.
Because binding to nucleolin compromises the ability of RPA to support
SV40 DNA replication, we suggest that the observed interaction reflects a mechanism whereby DNA replication is regulated after heat shock. The
relevance of this interaction to the regulation of cellular DNA
replication is indicated by the transient translocation in heated cells
of nucleolin from the nucleolus into the nucleoplasm with kinetics very
similar to those of SV40 DNA replication inhibition and of
RPA-nucleolin interaction. Because the targeting of RPA by nucleolin in
heated cells occurs in an environment that preserves the activity of
several essential DNA replication factors, active processes may
contribute to DNA replication inhibition to a larger degree than
presently thought. RPA-nucleolin interactions may reflect an early step
in the regulation of DNA replication, as nucleolin relocalized into the
nucleolus 1-2 h after heat exposure but cellular DNA replication
remained inhibited for up to 8 h. We propose that the nucleolus
functions as a heat sensor that uses nucleolin as a signaling molecule
to initiate inhibitory responses equivalent to a checkpoint.
To whom correspondence should be addressed. Tel.: 215-955-6473;
Fax: 215-955-2052; E-mail: george.iliakis@mail.tju.edu.
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