Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability to target photochemical adducts to specific genomic DNA sequences in cells is useful for studying DNA repair and mutagenesis in intact cells, and also as a potential mode of gene-specific therapy. Triple helix-forming DNA oligonucleotides linked to psoralen (psoTFOs) were designed to deliver UVA-induced psoralen photoadducts to two distinct sequences within the human interstitial collagenase gene. A primer extension assay demonstrated that the appropriate psoTFO selectively damages a collagenase cDNA target. Site-specific genomic psoTFO DNA adducts were detected by a single-strand ligation PCR assay. The adduct, formed at a single site by a psoTFO in purified genomic DNA, contrasted with the multiple sites that were damaged within the observed segment of the collagenase gene upon treatment with free psoralen and subsequent photoactivation. When treated with psoTFOs, both repair-deficient fibroblasts from xero- derma pigmentosum complementation group A and HT1080 fibrosarcoma cells exhibited site-specific DNA adducts following UVA irradiation. Addition of phorbol ester, a transcriptional activator of the collagenase gene, to xeroderma pigmentosum cells did not detectably alter the initial levels of damage produced by psoTFOs, suggesting that further stimulation of transcription neither improves accessibility of psoTFOs to their targets nor enhances removal of non-covalently bound psoTFOs.
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PMID:Triple helix-forming oligonucleotides target psoralen adducts to specific chromosomal sequences in human cells. 1057 73

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.
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PMID:TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin. 2560 38