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lower levels of the anti-oxidants superoxide dismutase and peroxidase [38]. In
accordance, homozygous bcl-2 knockout mice, an oncogene that regulates an antioxidant
pathway, turn gray with the second hair follicle cycle due to depletion of
melanocytes [39, 40]. Similarly, increased sensitivity of TTD melanoctyes to
oxidative damage could explain depletion of melanocytes and premature graying in
TTD mice. Second, sebaceous gland hyperplasia is frequently observed in males
past middle age [41] and also in TTD mice. In a certain type of male baldness,
sebaceous gland hyperplasia is associated with increased levels of GST, the key
enzyme in biosynthesis of the radical scavenger glutathion [42]. A similar
association between oxidative stress and sebaceous gland hyperplasia may exist in
TTD mice. Although systemic effects on melanocytes and sebocytes (e.g. honnonal
differences) are not excluded, the correlation with oxidative stress suggests that at
least pali of the clinical symptoms of TTD are caused by sensitivity to endogenous
(oxidative) DNA damage. In addition, accumulating evidence shows that oxidative
lesions playa role in the onset of CS symptoms. Considering the broad overlap
between CS and TID this could apply to TTD as well. Deficient repair of
endogenous lesions alone cannot explain the TTD symptoms because TTD mice
have a partial repair defect while completely NER deficient XPA mice are
phenotypically normal [43,44]. Previously, we proposed the repair/transcription
syndrome hypothesis to explain photosensitive TTD as a disease where deficient
repair of UV-induced lesions causes UV-sensitivity whereas the other clinical
symptoms result from an intrinsic transcription defect [18,19]. Theoretically
however, a combined defect in transcription and repair cannot be excluded. In this
respect, it is of interest to note that TTD is mostly associated with mild sensitivity to
genotoxic agents and a partial NER defect.
Endogenous lesions involved in TTD symptoms
To investigate the proposed role of defective DNA repair in the onset of
transcription-related symptoms, we crossed TTD mice with a partial NER defect
into a completely NER-deficient XPA background. XPAITTD double mutant mice
display growth retardation and kyphosis much more severe and earlier in onset,
causing death before weaning (unpublished data). Aparrantly, certain endogenous
DNA lesions, which are substrates for NER, are involved in transcription-related
symptoms of TTD. We suggest that the crippled transcription apparatus of TID
cells is particularly sensitive to these endogenous lesions. Thus, a complete NER
deficiency in XPA/TTD mice results in a higher level of lesions, a more severe
depletion of transcription and as a consequence more prominent clinical symptoms.
It would be very interesting to examine whether this principle of lesion-induced
transcription deficiency also applies to certain facets of nornlal aging. TTD mice
provide an excellent model to study the possible relationship between repair of
endogenous lesion, h'anscription capacity and progeroid symptoms in TTD and may
provide us insight into the molecular mechanism of aging.
116 Chapter 6