TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Abstract

Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in distinct clinical entities, including the cancerprone xeroderma pigmentosum (XP) and the multisystem disorder trichothiodystrophy (TTD), which share only cutaneous photosensitivity. Gene-expression profiles of primary dermal fibroblasts revealed overexpression of matrix metalloproteinase 1 (MMP-1), the gene encoding the metalloproteinase that degrades the interstitial collagens of the extracellular matrix (ECM), in TTD patients mutated in XPD compared with their healthy parents. The defect is observed in TTD and not in XP and is specific for fibroblasts, which are the main producers of dermal ECM. MMP-1 transcriptional up-regulation in TTD is caused by an erroneous signaling mediated by retinoic acid receptors on the MMP-1 promoter and leads to hypersecretion of active MMP-1 enzyme and degradation of collagen type I in the ECM of cell/tissue systems and TTD patient skin. In agreement with the well-known role of ECM in eliciting signaling events controlling cell behavior and tissue homeostasis, ECM alterations in TTD were shown to impact on the migration and wound-healing properties of patient dermal fibroblasts. The presence of a specific inhibitor of MMP activity was sufficient to restore normal cell migration, thus providing a potential approach for therapeutic strategies. This study highlights the relevance of ECM anomalies in TTD pathogenesis and in the phenotypic differences between TTD and XP. NER-defective disorders | TFIIH | transcription | MMP-1 | collagen degradation This work was supported by Associazione Italiana per la Ricerca sul Cancro Grant IG 13537 (to M.S.); Consiglio Nazionale delle Ricerche-Centre National de la Recherche Scientifique collaboration program (D.O. and E.C.); Ligue Contre le Cancer Grant 1FI11327OWGG (to J.-M.E. and E.C.); and the Consiglio Nazionale delle Ricerche/Ministro dell'Istruzione, dell 'Università e della Ricerca " Progetto d 'interesse invecchiamento" and the European Molecular Biology Organization (European Molecular Biology Organization-Short Term Fellowship ASTF 15-2008) (to D.O.).