Nucleic Acids Research, Vol 27, Issue 16 3276-3282, Copyright © 1999 by Oxford University Press
PP Van Sloun, JG Jansen, G Weeda, LH Mullenders, AA van Zeeland, PH Lohman and H Vrieling
In this study the role of nucleotide excision repair (NER) in protecting
mouse embryonic stem (ES) cells against the genotoxic effects of
UV-photolesions was analysed. Repair of cyclobutane pyrimidine dimers (CPD)
in transcribed genes could not be detected whereas the removal of (6-4)
photoproducts (6-4PP) was incomplete, already reaching its maximum (30%) 4
h after irradiation. Measurements of repair replication revealed a
saturation of NER activity at UV doses >5 J/m2 while at a lower dose
(2.5 J/m2) the repair kinetics were similar to those in murine embryonic
fibroblasts (MEFs). Cytotoxic and mutagenic effects of photolesions were
determined in ES cells differing in NER activity. ERCC1-deficient ES cells
were hypermutable (10-fold) compared to wild-type cells, indicating that at
physiologically relevant doses ES cells efficiently remove photolesions.
The effect of the NER deficiency on cytoxicity was only 2-fold. Exposure to
high UV doses (10 J/m2) resulted in a rapid and massive induction of
apoptosis. Possibly, to avoid the accumulation of mutated cells, ES cells
rely on the induction of a strong apoptotic response with a simultaneous
shutting down of NER activity.
ARTICLES
The role of nucleotide excision repair in protecting embryonic stem cells from genotoxic effects of UV-induced DNA damage
Department of Radiation Genetics and Chemical Mutagenesis-MGC, Leiden University Medical Center, PO Box 9503, 2300 RA Leiden, The Netherlands.
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