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in male sterility. As suggested by the authors, f32-tubulin expression may be reduced
in haywire mutants. Thus in fly, mouse and man, lowered expression of cl1lcial gene
products required at high levels in specific tissues or at critical stages of
development could explain many of the pleiotropic phenotypes. The TTD mouse
may provide an interesting model to study basal transcription in tenninally
differentiating tissues.
A putative role for endogenous lesions in the onset of TTD and CS
symptoms
CS and TTD are segmental progeroid syndromes because they display a number of
coherent aging-related symptoms, such as reduced life span, due to early
deterioration of the overall condition, early atTest of physical and sexual
development, cachexia, skeletal abnOlmalities, severe progressive neurological
dysfunction and an overall 'aged-like' appearance of patients early in life [48, 49).
Similarly, TTD mice have a reduced life span due to starvation and suffer from
osteoporosis, early graying, sebaceous gland hypelplasia, and reduced fertility all of
which resemble human aging (de Boer, manuscript in prep.). Extensive genetic data
from fungi to man indicates that modulation of oxidative stress plays a partial role
in relevant aging-phenotypes such as longevity and neuronal death [50). DNA repair
could well be such a modulator and recently, a possible involvement of endogenous
DNA lesions in the onset of the progeroid syndromes TID and CS was found.
TCR-defective CSB mice, that still have normal GGR were crossed into a totally
NER-deficient XPA background. Instead of very mild growth retardation observed
in male CSB mice, CSB/XPA double mutant mice suffer from severe runting and
die before weaning (van del' Horst, unpublished data). Similarly, several TTD
features were much more dramatic in an XPA-deficient background (de Boer,
unpublished data). Two-third of the double mutants die perinatally, and survivors
are runted and mostly die at an age of three to four weeks from starvation. The
severeness of symptoms in ITD/XPA and CSB/XPA double mutant mice indicates
that lesions, which are substrates for NER, cause at least part of the CS and TID
phenotypes. Oxidative lesions are promising candidates because some fonns of
oxidative damage are substrate for NER; they arise endogenously and have been
implicated in the aging process. However, the versatile NER pathway is involved in
removal of a plethora of different lesions, some of which may also arise
endogenously so other types of lesions cannot be excluded.
Tbe lack of an obvious phenotype of XPA mice [1,2] shows tbat NER deficiency
an sich does not cause TTD or CS-specific progeroid symptoms. The double
mutants demonsh·ate that it is rather a combination of persistence of endogenously
generated lesions and a CS- or TTD-specific deficiency. The dual function of TFIIH
in repair and basal h·anscription, and of CSB in TCR in mind, we speculate that
endogenously arising DNA lesions may hamper basal transcription in CS and TTD
cells, with aging-like clinical symptoms as consequence in affected mice or patients.
NER-deficient mouse models 41