Translational infidelity as a common pathomechanism in Trichothiodystrophy

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by a wide spectrum of symptoms including photosensitivity, ichthyosis, brittle hair and nails, intellectual impairment, decreased fertility and short stature. The diagnostic hallmark of TTD is a “tiger tail” pattern which can be observed in the hair structure in polarizing microscope. TTD is caused by distinct mutations in different genes encoding for the subunit of TFIIH (XPB, XPD, p8), TFIIEβ, TTDN1, RNF113 and tRNA synthetases. This work investigated a common pathomechanism in both XPD and TFIIEβ mutated TTD cells, which give rise to a photosensitive and a non-photosensitive form of TTD, respectively. TFIIH and TFIIE are interaction partners during the initiation of RNA polymerase II transcription. Recently, TFIIH has been identified as an essential elongation factor during RNA polymerase I transcription. Thus, the potential role of TFIIE in RNA polymerase I transcription was examined. By using localization studies and ChIP analysis this work unraveled a so far unknown role of TFIIE in RNA polymerase I transcription. TFIIEβ mutated TTD cells display furthermore disturbance in rRNA processing, reduced representation of ribosomal proteins in the 40S subunit and in final maturation of the 40S ribosomal subunit. Remarkably, all TTD cell lines indicated elevated error-rate during translation. While increased translational infidelity in TFIIEβ mutated TTD cells can be explained by disturbed ribosomal biogenesis, the molecular base of the elevated translational inaccuracy in XPD mutated TTD cells awaits further analysis. However, translational infidelity is followed by disturbance in protein homeostasis in both XPD and TFIIEβ mutated TTD cells. Since this pathophysiology characterizing TTD cells is not observed in XP cells, this work hypothesizes that loss of translational accuracy might be the common pathomechanism in TTD. Our work extends the previous view of TTD as not only a DNA-repair / transcription syndrome but furthermore to a translation syndrome.