Germline mutations in the DNA repair helicase XPD can cause the diseases xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). XP patients bear an increased risk of skin cancer including melanoma. This is not observed for TTD patients despite DNA repair defects. To examine whether TTD cells harbor features counteracting tumorigenesis, we developed a TTD melanoma cell model containing the XPD variant R722W. Intriguingly, TTD melanoma cells exhibited reduced proliferation and an increased signature of the melanocyte lineage factor MITF, along with a strong basal upregulation of REDD2, an inhibitor of the mTOR/S6K/4EBP1-dependent messenger RNA (mRNA) translation machinery. REDD2 levels were partially driven by MITF and contributed to reduced melanoma proliferation. In a TTD model for melanocytes-the progenitor cells of melanoma-the MITF gene signature was also increased, but here without affecting REDD2 expression. However, ribosomal protein synthesis was reduced particularly in R722W melanocytes after UV stress, indicating a compromised mRNA translation machinery. Impaired translation was also demonstrated for the TTD XPD variant A725P, but not for an XP variant. Concludingly, the impaired translation and reduced fitness observed in TTD melanocytes and melanoma cells, particularly after UV stress, offer a possible explanation why TTD patients do not develop melanomas.
© The Author(s) 2025. Published by Oxford University Press.