期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：5
页码：1499-1504
DOI：10.1073/pnas.1416181112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDespite exhibiting different phenotypes, the UV-sensitive syndromes trichothiodystrophy (TTD) and xeroderma pigmentosum (XP) result from the same mutated genes encoding specific subunits of the DNA-repair/transcription factor TFIIH. The widely accepted notion is that XP cancer proneness results from mutations interfering with DNA repair, whereas TTD clinical hallmarks (namely, hair anomalies, physical and mental retardation, and premature aging) are because of transcriptional alterations. The present study identifies a TTD-specific overexpression of matrix metalloproteinase 1, leading to collagen I degradation in patient skin. This finding explains the clinical features distinguishing TTD from XP (i.e. bone alterations, pregnancy abnormalities and likely lack of skin cancer despite the accumulation of unrepaired DNA lesions) and the features that TTD shares with osteogenesis imperfecta caused by COL1 mutations. 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.
