Nucleic Acids Research, Vol 24, Issue 23 4653-4659, Copyright © 1996 by Oxford University Press
MF van Oosterwijk, R Filon, WH Kalle, LH Mullenders and AA van Zeeland
Nucleotide excision repair (NER) mechanism is the major pathway responsible
for the removal of a large variety of bulky lesions from the genome. Two
different NER subpathways have been identified, i.e. the
transcription-coupled and the global genome repair pathways. For DNA-damage
induced by ultraviolet light both transcription-coupled repair and global
genome repair are essential to confer resistance to cytotoxic effects. To
gain further insight into the contribution of NER subpathways in the repair
of bulky lesions and in their prevention of biological effects we measured
the rate of repair of dG-C8-AF in active and inactive genes in normal human
cells, XP-C cells (only transcription-coupled repair) and XP-A cells
(completely NER-deficient) exposed to NA-AAF. XP-C cells are only slightly
more sensitive to NA- AAF than normal cells and, like normal cells, they
are able to recover RNA synthesis repressed by the treatment. In contrast,
XP-A cells are sensitive to NA-AAF and unable to recover from RNA synthesis
inhibition. Repair of dG-C8-AF in the active ADA gene proceeds in a
biphasic way and without strand specificity, with a subclass of lesions
quickly repaired during the first 8 h after treatment. Repair in the
inactive 754 gene occurs more slowly than in the ADA gene. In XP-C cells,
repair of dG-C8-AF in the ADA gene is confined to the transcribed strand
and occurs at about half the rate of repair seen in normal cells. Repair in
the inactive 754 gene in XP-C cells is virtually absent. Consistent with
these results we found that repair replication in XP-C is drastically
reduced when compared with normal cells and abolished by alpha-amanitin
indicating that the repair in XP- C cells is mediated by
transcription-coupled repair only. Our data suggest that dG-C8-AF is a
target for transcription-coupled repair and that this repair pathway is the
main pathway or recovery of RNA synthesis inhibition conferring resistance
to cytotoxic effects of NA- AAF. In spite of this, repair of dG-C8-AF in
active genes in normal cells by transcription-coupled repair and global
genome repair is not additive, but dominated by global genome repair. This
indicates that the subset of lesions which are capable of stalling RNA
polymerase II, and are, therefore, a substrate for TCR, are also the
lesions which are very efficiently recognized by the global genome repair
system.
ARTICLES
The sensitivity of human fibroblasts to N-acetoxy-2-acetylaminofluorene is determined by the extent of transcription-coupled repair, and/or their capability to counteract RNA synthesis inhibition
MGC-Department of Radiation Genetics and Chemical Mutagenesis, Leiden University, The Netherlands.
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