Mus musculus Transcriptome or Gene expression

Germline mutations in the DNA repair helicase XPD cause the diseases xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome. XP patients bear an increased risk of developing skin cancer including melanoma, even at young age. This is not observed for TTD patients despite DNA repair defects. To examine whether TTD cells harbour features counteracting tumorigenesis, we developed genetically engineered models of TTD murine melanocytes containing the XPD-R722W mutation. As controls, cells expressing the XP-causing D234N mutation or wildtype XPD were generated, respectively. RNA sequencing of these cell lines in absence or presence of UV revealed a strong upregulation of a differentiation-associated MITF gene signature specifically in TTD melanocytes, as well as UV-dependent alterations in translation-associated pathways, which could be confirmed by proteomic analyses. Concludingly, TTD mutant melanocytes exhibit translation inhibition and therefore reduced fitness, particularly under UV exposure.