title: 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 cancer-prone 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.
authors.affiliation: Istituto di Genetica Molecolare Consiglio Nazionale delle Ricerche, Pavia 27100, Italy;
authors.forename: Lavinia
authors.initials: L
authors.lastname: Arseni
authors.affiliation: Istituto di Genetica Molecolare Consiglio Nazionale delle Ricerche, Pavia 27100, Italy;
authors.forename: Manuela
authors.initials: M
authors.lastname: Lanzafame
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch Cedex 67404, Strasbourg, France;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Compe
authors.affiliation: Bambino Gesù Children's Hospital and.
authors.forename: Paola
authors.initials: P
authors.lastname: Fortugno
authors.affiliation: Istituto di Genetica Molecolare Consiglio Nazionale delle Ricerche, Pavia 27100, Italy;
authors.forename: António
authors.initials: A
authors.lastname: Afonso-Barroso
authors.affiliation: Istituto di Genetica Molecolare Consiglio Nazionale delle Ricerche, Pavia 27100, Italy;
authors.forename: Fiorenzo A
authors.initials: FA
authors.lastname: Peverali
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
authors.affiliation: Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome 00165, Italy; and.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch Cedex 67404, Strasbourg, France;
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.affiliation: Istituto di Genetica Molecolare Consiglio Nazionale delle Ricerche, Pavia 27100, Italy; stefanini@igm.cnr.it orioli@igm.cnr.it.
authors.forename: Miria
authors.initials: M
authors.lastname: Stefanini
authors.affiliation: Istituto di Genetica Molecolare Consiglio Nazionale delle Ricerche, Pavia 27100, Italy; stefanini@igm.cnr.it orioli@igm.cnr.it.
authors.forename: Donata
authors.initials: D
authors.lastname: Orioli
mesh_terms: D005109:Extracellular Matrix / Q000473:pathology*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D051758:Transcription Factor TFIIH / Q000502:physiology*; D054463:Trichothiodystrophy Syndromes / Q000201:enzymology* / Q000473:pathology; D014945:Wound Healing
chemical_list: D018168:Receptors, Retinoic Acid; D051758:Transcription Factor TFIIH; D020781:Matrix Metalloproteinase 1
keywords: MMP-1; NER-defective disorders; TFIIH; collagen degradation; transcription