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Reduced levels of prostaglandin I2 synthase: a distinctive feature of the cancer-free trichothiodystrophy

Significance Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), which may arise from mutations in the same genes, are distinct clinical entities with opposite skin cancer predisposition. Whereas XP is characterized by cutaneous photosensitivity and cancer proneness frequently associated with neurodegeneration, TTD shows hair anomalies, physical and mental retardation, and, in 50% of cases, cutaneous photosensitivity but no skin cancer despite the accumulation of unrepaired ultraviolet-induced DNA lesions. This study identifies a TTD-specific transcription deregulation of PTGIS (prostaglandin I2 synthase) that results in reduced levels of prostaglandin I2. Reduced PTGIS is found in all TTD but not in XP patients, thus representing a biomarker for this disorder. The cancer-free photosensitive trichothiodystrophy (PS-TTD) and the cancer-prone xeroderma pigmentosum (XP) are rare monogenic disorders that can arise from mutations in the same genes, namely ERCC2/XPD or ERCC3/XPB. Both XPD and XPB proteins belong to the 10-subunit complex transcription factor IIH (TFIIH) that plays a key role in transcription and nucleotide excision repair, the DNA repair pathway devoted to the removal of ultraviolet-induced DNA lesions. Compelling evidence suggests that mutations affecting the DNA repair activity of TFIIH are responsible for the pathological features of XP, whereas those also impairing transcription give rise to TTD. By adopting a relatives-based whole transcriptome sequencing approach followed by specific gene expression profiling in primary fibroblasts from a large cohort of TTD or XP cases with mutations in ERCC2/XPD gene, we identify the expression alterations specific for TTD primary dermal fibroblasts. While most of these transcription deregulations do not impact on the protein level, very low amounts of prostaglandin I2 synthase (PTGIS) are found in TTD cells. PTGIS catalyzes the last step of prostaglandin I2 synthesis, a potent vasodilator and inhibitor of platelet aggregation. Its reduction characterizes all TTD cases so far investigated, both the PS-TTD with mutations in TFIIH coding genes as well as the nonphotosensitive (NPS)-TTD. A severe impairment of TFIIH and RNA polymerase II recruitment on the PTGIS promoter is found in TTD but not in XP cells. Thus, PTGIS represents a biomarker that combines all PS- and NPS-TTD cases and distinguishes them from XP.