Here we show that XPG mutation leading to severe XP/CS, but not to XP, affects RNA polymerase I transcription and strongly impacts the phosphorylation of the eukaryotic initiation factor 2 alpha (eIF2alpha), thereby inhibiting overall cap-dependent translation and favoring internal ribosomal entry site (IRES) translation. This evidence concerns the gene EIF2S1 and Cowden syndrome 1.