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NER DEFICIENCY AND GENOTOXIC SENSITIVITY
A direct clinical consequence of a deficiency in the NER system is the marked UV
(sun) sensitivity and, in XP patients, strong predisposition for tumor development
on sun-exposed skin [10]. At the cellular level, UV irradiation induces chemical
alterations in the DNA, predominantly cyclobutane pyrimidine dimers (CPDs) and
6-4 photoproducts (6-4PPs). CPDs are repaired in a fast and complete fashion by the
TCR machinery in the transcribed strand of active genes but elsewhere in the
genome, repair by GGR is slower and less efficient. The less abundant 6-4PPs are
removed very rapidly and genome-wide by GGR and in its absence by TCR in the
transcribed sequences. Some important differences exist in the activity of NER
between mouse and man. Notably, CPDs (but not 6-4PPs and many chemical
adducts) are hardly removed from the non-transcribed sequences in rodents [II].
However, this difference does not appear to have dramatic consequences since
repair parameters in mouse embryonic fibroblasts (MEFs) from repair-deficient
mice such as unscheduled DNA synthesis (UDS), recovery of RNA synthesis after
UV-irradiation and sensitivity to UV-light correlate very well with those of human
patient fibroblasts (see Table I).
In vivo, UV -inadiation causes an acute inflammatory reaction in the skin,
characterized by cutaneous vasodilatation (erythema), followed by increase in the
vascular permeability with exudation of fluid (edema). To man this is best known as
sunburn after a sunny day on the beach. Analysis of the minimal UV-dose to induce
erythema/edema (MED) in mice demonstrated that persistence of photoproducts,
particularly in transcriptionally active DNA, triggers the pathway that leads to
erythema and edema in the irradiated skin. Consequently, XPA- and CSB-deficient
mice, incapable of repairing photo lesions from actively transcribed genes, have a
marked reduction in MED [5, 12, de Boer et aI., submitted]. For CSB-deficient mice
this response may be somewhat more exaggerated when compared with the human
disorder because in the mouse model there is no contribution of GGR to the
elimination of CPD lesions from transcribed sequences, whereas in the human
situation -in the absence of TCR- GGR may still remove a significant fraction of
these tr'anscription-blocking lesions albeit more slowly. In contr'ast, XPC-deficient
mice with a GGR defect have a MED in the wild-type range [13, de Boer et aI.,
submitted]. In accordance, nine XP-C patients showed MED within the normal
range of healthy humans [14]. When translating the observations from the murine to
the human condition one should take into account that the absence of CPD repair by
murine GGR makes a wild-type mouse in this regard more like an XPC mutant.
Consequently, the difference between the wild-type and XPC states in the mouse is
smaller compared to humans.
30 Chapter 2