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J Biol Chem, Vol. 274, Issue 45, 32520-32527, November 5, 1999
From the Department of Biochemistry and Molecular Biology, the
Indiana University Cancer Center, Walther Oncology Center, Indiana
University School of Medicine, Indianapolis, Indiana 46202
Cells exposed to UV irradiation are predominantly
arrested at S-phase as well as at the G1/S boundary
while repair occurs. It is not known how UV irradiation induces S-phase
arrest and yet permits DNA repair; however, UV-induced inhibition of
replication is efficiently reversed by the addition of replication
protein A (RPA), suggesting a role for RPA in this regulatory event.
Here, we show evidence that DNA-dependent protein kinase
(DNA-PK), plays a role in UV-induced replication arrest. DNA synthesis
of M059K (DNA-PK catalytic subunit-positive (DNA-PKcs+)),
as measured by [3H]thymidine incorporation, was
significantly arrested by 4 h following UV irradiation, whereas
M059J (DNA-PKcs
) cells were much less affected. Similar
results were obtained with the in vitro replication
reactions where immediate replication arrest occurred in
DNA-PKcs+ cells following UV irradiation, and only a
gradual decrease in replication activity was observed in
DNA-PKcs cells. Reversal of replication arrest was
observed at 8 h following UV irradiation in DNA-PKcs+
cells but not in DNA-PKcs cells. Reversal of UV-induced
replication arrest was also observed in vitro by the
addition of a DNA-PK inhibitor, wortmannin, or by immunodepletion of
DNA-PKcs, supporting a positive role for DNA-PK in damage-induced
replication arrest. The RPA-containing fraction from UV-irradiated
DNA-PKcs+ cells poorly supported DNA replication, whereas
the replication activity of the RPA-containing fraction from
DNA-PKcs cells was not affected by UV, suggesting that
DNA-PKcs may be involved in UV-induced replication arrest through
modulation of RPA activity. Together, our results strongly suggest a
role for DNA-PK in S-phase (replication) arrest in response to UV irradiation.
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