PMC:1584416 / 17150-19435 JSONTXT

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XpdTTD/KO hemizygous cells were thus used as the baseline on which to compare the activity of compound heterozygous cells. Relative to XpdTTD/KO hemizygote cells, UV survival was improved by the homozygous lethal Xpd†XPCS allele in XpdTTD/†XPCS compound heterozygous cells and to a lesser degree by the Xpd†XP allele (Figure 4A). Because of embryonic and cellular lethality, we were unable to test UV survival associated exclusively with the Xpd†XPCS or Xpd†XP alleles. However, homozygous XPDXP (XPDR683W) and hemizygous XPDXPCS (XPDG602D) human cells are known to be highly sensitive to UV [19,25], as are cells from a homozygous viable XpdXPCS/XPCS (XPDG602D/G602D) mouse model (Figure 4A, dotted line) [23]. Thus, the survival of XpdTTD/†XPCS (and XpdTTD/†XP) cells likely represents a level of UV resistance that neither mutant allele can impart on its own (Table 2). Significant effects of compound heterozygosity on NER subpathways relative to XpdTTD/KO cells were observed in XpdTTD/†XP cells but only for UV-UDS activity. Finally, none of the mutant TFIIH combinations (carrying alterations associated with TTD [XPDR722W], XPCS [XPDG602D], or XP [XPDR683W]) exhibited synergism in an in vitro NER reaction reconstituted with different mutant TFIIH complexes (Figure 4D). Taken together, these data are consistent with interallelic complementation of UV sensitivity in cells but underscore the lack of any correlation between UV-related repair characteristics and TTD progeroid phenotypes in animal 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