Nucleic Acids Research, Vol 27, Issue 3 803-809, Copyright © 1999 by Oxford University Press
JM Larner, H Lee, RD Little, PA Dijkwel, CL Schildkraut and JL Hamlin
An asynchronous culture of mammalian cells responds acutely to ionizing
radiation by inhibiting the overall rate of DNA replication by
approximately 50% for a period of several hours, presumably to allow time
to repair DNA damage. At low and moderate doses, this S phase
damage-sensing (SDS) pathway appears to function primarily at the level of
individual origins of replication, with only a modest inhibition of chain
elongation per se. We have shown previously that the majority of the
inhibition observed in an asynchronous culture can be accounted for by late
G1cells that were within 2-3 h of entering the S period at the time of
irradiation and which then fail to do so. A much smaller effect was
observed on the overall rate of replication in cells that had already
entered the S phase. This raised the question whether origins of
replication that are activated within S phase per se are inhibited in
response to ionizing radiation. Here we have used a two-dimensional gel
replicon mapping strategy to show that cells with an intact SDS pathway
completely down-regulate initiation in both early- and late- firing rDNA
origins in human cells. We also show that initiation in mid- or late-firing
rDNA origins is not inhibited in cells from patients with ataxia
telangiectasia, confirming the suggestion that these individuals lack the
SDS pathway.
ARTICLES
Radiation down-regulates replication origin activity throughout the S phase in mammalian cells
Department of Therapeutic Radiology and Oncology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA, jlh2d@virginia.edu
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