Year: 2025
Type: conference-abstract
Abstract: 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 harbor features counteracting tumorigenesis, we developed a TTD melanoma cell model containing the XPD variant R722W.Intriguingly, TTD melanoma cells exhibited reduced pro-tumorigenic features and an increased signature of the melanocyte lineage differentiation factor MITF, which went along with a strong basal upregulation of REDD2, an inhibitor of the mTOR/S6K/4EBP1 dependent protein translation machinery.REDD2 levels were partially driven by MITF, increased under UV exposure, and contributed to the reduced melanoma proliferation. © 2025 Deutsche Dermatologische Gesellschaft (DDG).To investigate whether similar processes are affected in melanocytes -the progenitor cell type of melanomawe developed a TTD melanocyte model.Again, the MITF gene signature was increased, this time without affecting REDD2 expression.However, protein translation analyses revealed reduced ribosomal protein synthesis particularly in R722W melanocytes after UV stress, indicating a compromised protein translation machinery.Impaired protein translation was also demonstrated for the TTD XPD variant A725P, but not for the XPD variant D234N that causes XP.Concludingly, although effectors of R722W partially differ between melanoma cells and melanocytes, they result in translation inhibition and therefore reduced fitness, particularly under UV exposure.This may limit the probability of UV-driven tumorigenesis and offers an explanation why TTD patients do not develop melanomas.
DOI: 10.1111/ddg.15735_g
Language: German
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4408942151