TFIIH in Transcription and Repair: Mechanisms of XPD Disease Pleiotropy
We observed differences in the ability of XpdTTD versus homozygous lethal Xpd†XPCS and Xpd†XP alleles to function in two transcription-related phenotypes separated in the organism by both time and space: embryonic lethality and terminal differentiation of enucleating skin and blood cells. The preblastocyst-stage homozygous lethality shared by the XpdKO, Xpd†XPCS, and Xpd†XP alleles most likely reflects a defect in basal transcription that is incompatible with life. In XpdTTD/ †XPCS and XpdTTD/ †XP compound heterozygous mice, embryonic lethality was fully rescued by the XpdTTD allele. Because embryonic lethality was also fully rescued in XpdTTD/KO hemizygous mice, the XpdTTD allele can be considered as wt and thus dominant to each of the homozygous lethal alleles (XpdKO, Xpd†XPCS, and Xpd†XP) with respect to this particular phenotype (Table 2).
TTD-specific cutaneous and anaemic features, on the other hand, are thought to result from a specific kind of transcriptional insufficiency caused by depletion of unstable TFIIH during the terminal differentiation of skin, hair-shaft, and blood cells [16,24]. In compound heterozygous mice, both homozygous lethal Xpd†XPCS and Xpd†XP alleles were able to alleviate XpdTTD-specific cutaneous and anaemic features and can thus be defined as dominant over the XpdTTD allele with respect to these phenotypes. We conclude that the defects leading to embryonic lethality and aberrant terminal differentiation of the skin, hair, and blood represent two qualitatively and/or quantitatively different transcriptional deficiencies. During early embryonic development, XpdTTD is dominant over the Xpd†XPCS and Xpd†XP alleles, whereas later in the ontogenesis of skin, hair-shaft, and blood cells, the situation is reversed.
In its role in the repair of UV photolesions, the Xpd†XPCS allele imparted a clear UV survival benefit over a single XpdTTD allele or two XpdXPCS alleles independent of expression levels, which is consistent with interallelic complementation. However, the observation that no other cellular or biochemical UV-related parameters were improved in XpdTTD/ †XPCS argues against complementation of this repair activity in the rescue of TTD progeroid symptoms in vivo.