2021
|
Lanzafame M; Branca G; Landi C; Qiang M; Vaz B; Nardo T; Ferri D; Mura M; Iben S; Stefanini M; Peverali FA; Bini L; Orioli D Cockayne syndrome group A and ferrochelatase finely tune ribosomal gene transcription and its response to UV irradiation Journal Article In: Nucleic Acids Research, vol. 49, iss. 19, no. 10911, pp. 10930, 2021. @article{%a1:%Ybvz,
title = {Cockayne syndrome group A and ferrochelatase finely tune ribosomal gene transcription and its response to UV irradiation},
author = {Lanzafame M and Branca G and Landi C and Qiang M and Vaz B and Nardo T and Ferri D and Mura M and Iben S and Stefanini M and Peverali FA and Bini L and Orioli D},
url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkab819/6377400},
doi = {10.1093/nar/gkab819},
year = {2021},
date = {2021-10-28},
urldate = {2021-10-28},
journal = {Nucleic Acids Research},
volume = {49},
number = {10911},
issue = {19},
pages = {10930},
abstract = {CSA and CSB proteins are key players in transcription-coupled nucleotide excision repair (TC-NER) pathway that removes UV-induced DNA lesions from the transcribed strands of expressed genes. Additionally, CS proteins play relevant but still elusive roles in other cellular pathways whose alteration may explain neurodegeneration and progeroid features in Cockayne syndrome (CS). Here we identify a CS-containing chromatin-associated protein complex that modulates rRNA transcription. Besides RNA polymerase I (RNAP1) and specific ribosomal proteins (RPs), the complex includes ferrochelatase (FECH), a well-known mitochondrial enzyme whose deficiency causes erythropoietic protoporphyria (EPP). Impairment of either CSA or FECH functionality leads to reduced RNAP1 occupancy on rDNA promoter that is associated to reduced 47S pre-rRNA transcription. In addition, reduced FECH expression leads to an abnormal accumulation of 18S rRNA that in primary dermal fibroblasts from CS and EPP patients results in opposed rRNA amounts. After cell irradiation with UV light, CSA triggers the dissociation of the CSA-FECH-CSB-RNAP1-RPs complex from the chromatin while it stabilizes its binding to FECH. Besides disclosing a function for FECH within nucleoli, this study sheds light on the still unknown mechanisms through which CSA modulates rRNA transcription.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
CSA and CSB proteins are key players in transcription-coupled nucleotide excision repair (TC-NER) pathway that removes UV-induced DNA lesions from the transcribed strands of expressed genes. Additionally, CS proteins play relevant but still elusive roles in other cellular pathways whose alteration may explain neurodegeneration and progeroid features in Cockayne syndrome (CS). Here we identify a CS-containing chromatin-associated protein complex that modulates rRNA transcription. Besides RNA polymerase I (RNAP1) and specific ribosomal proteins (RPs), the complex includes ferrochelatase (FECH), a well-known mitochondrial enzyme whose deficiency causes erythropoietic protoporphyria (EPP). Impairment of either CSA or FECH functionality leads to reduced RNAP1 occupancy on rDNA promoter that is associated to reduced 47S pre-rRNA transcription. In addition, reduced FECH expression leads to an abnormal accumulation of 18S rRNA that in primary dermal fibroblasts from CS and EPP patients results in opposed rRNA amounts. After cell irradiation with UV light, CSA triggers the dissociation of the CSA-FECH-CSB-RNAP1-RPs complex from the chromatin while it stabilizes its binding to FECH. Besides disclosing a function for FECH within nucleoli, this study sheds light on the still unknown mechanisms through which CSA modulates rRNA transcription. |
Lombardi A; Arseni L; Carriero R; Compe E; Botta E; Ferri D; Uggè M; Biamonti G; Peverali FA; Bione S; Orioli D Reduced levels of prostaglandin I 2 synthase: a distinctive feature of the cancer-free trichothiodystrophy Journal Article In: Proceedings of the National Academy of Sciences of the United States of America., vol. 118, no. 26, 2021. @article{%a1:%Ybv,
title = {Reduced levels of prostaglandin I 2 synthase: a distinctive feature of the cancer-free trichothiodystrophy},
author = {Lombardi A and Arseni L and Carriero R and Compe E and Botta E and Ferri D and Uggè M and Biamonti G and Peverali FA and Bione S and Orioli D},
url = {https://www.pnas.org/content/118/26/e2024502118.long},
doi = {10.1073/pnas.2024502118},
year = {2021},
date = {2021-08-25},
journal = {Proceedings of the National Academy of Sciences of the United States of America.},
volume = {118},
number = {26},
abstract = {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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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. |
2019
|
Crociara P; Chieppa MN; Costassa EV; Berrone E; Gallo M; Faro ML; Pintore MD; Iulini B; D'Angelo A; Perona G; Botter A; Formicola D; Rainoldi A; Paulis M; Vezzoni P; Meli F; Peverali FA; Bendotti C; Trolese MC; Pasetto L; Bonetto V; Lazzari G; Duchi R; Perota A; Lagutina I; Quadalti C; Gennero MS; Dezzutto D; Desiato R; Boido M; Ghibaudi M; Valentini MC; Caramelli M; Galli C; Casalone C; Corona C Motor neuron degeneration, severe myopathy and TDP-43 increase in a transgenic pig model of SOD1-linked familiar ALS. Journal Article In: Neurobiology of disease, vol. 124, pp. 263-275, 2019. @article{%a1:%Y%z,
title = {Motor neuron degeneration, severe myopathy and TDP-43 increase in a transgenic pig model of SOD1-linked familiar ALS.},
author = {Crociara P and Chieppa MN and Costassa EV and Berrone E and Gallo M and Faro ML and Pintore MD and Iulini B and D'Angelo A and Perona G and Botter A and Formicola D and Rainoldi A and Paulis M and Vezzoni P and Meli F and Peverali FA and Bendotti C and Trolese MC and Pasetto L and Bonetto V and Lazzari G and Duchi R and Perota A and Lagutina I and Quadalti C and Gennero MS and Dezzutto D and Desiato R and Boido M and Ghibaudi M and Valentini MC and Caramelli M and Galli C and Casalone C and Corona C},
url = {https://www.sciencedirect.com/science/article/pii/S0969996118307526?via%3Dihub},
doi = {10.1016/j.nbd.2018.11.021},
year = {2019},
date = {2019-04-30},
journal = {Neurobiology of disease},
volume = {124},
pages = {263-275},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neural disorder gradually leading to paralysis of the whole body. Alterations in superoxide dismutase SOD1 gene have been linked with several variants of familial ALS. Here, we investigated a transgenic (Tg) cloned swine model expressing the human pathological hSOD1G93A allele. As in patients, these Tg pigs transmitted the disease to the progeny with an autosomal dominant trait and showed ALS onset from about 27 months of age. Post mortem analysis revealed motor neuron (MN) degeneration, gliosis and hSOD1 protein aggregates in brainstem and spinal cord. Severe skeletal muscle pathology including necrosis and inflammation was observed at the end stage, as well. Remarkably, as in human patients, these Tg pigs showed a quite long presymptomatic phase in which gradually increasing amounts of TDP-43 were detected in peripheral blood mononuclear cells. Thus, this transgenic swine model opens the unique opportunity to investigate ALS biomarkers even before disease onset other than testing novel drugs and possible medical devices.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Amyotrophic Lateral Sclerosis (ALS) is a neural disorder gradually leading to paralysis of the whole body. Alterations in superoxide dismutase SOD1 gene have been linked with several variants of familial ALS. Here, we investigated a transgenic (Tg) cloned swine model expressing the human pathological hSOD1G93A allele. As in patients, these Tg pigs transmitted the disease to the progeny with an autosomal dominant trait and showed ALS onset from about 27 months of age. Post mortem analysis revealed motor neuron (MN) degeneration, gliosis and hSOD1 protein aggregates in brainstem and spinal cord. Severe skeletal muscle pathology including necrosis and inflammation was observed at the end stage, as well. Remarkably, as in human patients, these Tg pigs showed a quite long presymptomatic phase in which gradually increasing amounts of TDP-43 were detected in peripheral blood mononuclear cells. Thus, this transgenic swine model opens the unique opportunity to investigate ALS biomarkers even before disease onset other than testing novel drugs and possible medical devices. |
2016
|
Kuschal C; Botta E; Orioli D; Digiovanna JJ; Seneca S; Keymolen K; Tamura D; Heller E; Khan SG; Caligiuri G; Lanzafame M; Nardo T; Ricotti R; Peverali FA; Stephens R; Zhao Y; Lehmann AR; Baranello L; Levens D; Kraemer KH; Stefanini M GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy. Journal Article In: American Journal of Human Genetics, vol. 98, no. 4, pp. 627-642, 2016. @article{%a1:%Y_290,
title = {GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy.},
author = {Kuschal C and Botta E and Orioli D and Digiovanna JJ and Seneca S and Keymolen K and Tamura D and Heller E and Khan SG and Caligiuri G and Lanzafame M and Nardo T and Ricotti R and Peverali FA and Stephens R and Zhao Y and Lehmann AR and Baranello L and Levens D and Kraemer KH and Stefanini M},
url = {http://www.sciencedirect.com/science/article/pii/S0002929716000598},
doi = {10.1016/j.ajhg.2016.02.008},
year = {2016},
date = {2016-04-16},
journal = {American Journal of Human Genetics},
volume = {98},
number = {4},
pages = {627-642},
abstract = {The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEbeta). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEalpha and TFIIEbeta) as well as decreased phosphorylation of TFIIEalpha in cells from both children. Interestingly, decreased phosphorylation of TFIIEalpha was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP. Copyright 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEbeta). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEalpha and TFIIEbeta) as well as decreased phosphorylation of TFIIEalpha in cells from both children. Interestingly, decreased phosphorylation of TFIIEalpha was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP. Copyright 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
Dell'Orco M; Milani P; Arrigoni L; Pansarasa O; Sardone V; Maffioli E; Polveraccio F; Bordoni M; Diamanti L; Peverali FA; Tedeschi G; Cereda C Hydrogen peroxide-dependent oxidative stress induces SOD1 transcription gene is independent from Nrf2 transcription factor in a cellular model of neurodegeneration. Journal Article In: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, vol. 1859, no. 2, pp. 315-323, 2016. @article{%a1:%Y_266,
title = {Hydrogen peroxide-dependent oxidative stress induces SOD1 transcription gene is independent from Nrf2 transcription factor in a cellular model of neurodegeneration.},
author = {{Dell'Orco M} and Milani P and Arrigoni L and Pansarasa O and Sardone V and Maffioli E and Polveraccio F and Bordoni M and Diamanti L and Peverali FA and Tedeschi G and Cereda C},
url = {http://www.sciencedirect.com/science/article/pii/S1874939915002485},
doi = {10.1016/j.bbagrm.2015.11.009},
year = {2016},
date = {2016-02-25},
journal = {Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms},
volume = {1859},
number = {2},
pages = {315-323},
abstract = {BACKGROUND: It is still unclear whether oxidative stress (OS) is a disease consequence or is directly involved in the etiology of neurodegenerative disorders (NDs) onset and/or progression; however, many of these conditions are associated with increased levels of oxidation markers and damaged cell components. Previously we demonstrated the accumulation of reactive oxygen species (ROS) and increased SOD1 gene expression within H2O2 SH-SY5Y treated cells recapitulating pathological features of Amyotrophic Lateral Sclerosis (ALS). Since we observed a post-transcriptional regulation of SOD1 gene in this cellular model of ALS, we investigated the transcriptional regulation of SOD1 mRNA under oxidative stress (OS). RESULTS: In response to H2O2 treatment, PolII increased its association to SOD1 promoter. Electrophoretic mobility shift assays (EMSA) and mass spectrometry analyses on SOD1 promoter highlighted the formation of a transcriptional complex bound to the ARE sequences. WB analyses showed that in our in vitro model, H2O2 exposure increases Nrf2 nuclear fraction while IP experiments confirmed its phosphorylation and release from Keap1 inhibition. However, H2O2 treatment did not modify Nrf2 binding on SOD1 promoter, which seems to be regulated by different TFs. CONCLUSIONS: Although our data suggest that SOD1 is transcriptionally regulated in response to OS, Nrf2 does not appear to associate with SOD1 promoter in this model of ALS. Our results open new perspectives in the comprehension of two key antioxidant pathways involved in neurodegeneration. Copyright 2015. Published by Elsevier B.V.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: It is still unclear whether oxidative stress (OS) is a disease consequence or is directly involved in the etiology of neurodegenerative disorders (NDs) onset and/or progression; however, many of these conditions are associated with increased levels of oxidation markers and damaged cell components. Previously we demonstrated the accumulation of reactive oxygen species (ROS) and increased SOD1 gene expression within H2O2 SH-SY5Y treated cells recapitulating pathological features of Amyotrophic Lateral Sclerosis (ALS). Since we observed a post-transcriptional regulation of SOD1 gene in this cellular model of ALS, we investigated the transcriptional regulation of SOD1 mRNA under oxidative stress (OS). RESULTS: In response to H2O2 treatment, PolII increased its association to SOD1 promoter. Electrophoretic mobility shift assays (EMSA) and mass spectrometry analyses on SOD1 promoter highlighted the formation of a transcriptional complex bound to the ARE sequences. WB analyses showed that in our in vitro model, H2O2 exposure increases Nrf2 nuclear fraction while IP experiments confirmed its phosphorylation and release from Keap1 inhibition. However, H2O2 treatment did not modify Nrf2 binding on SOD1 promoter, which seems to be regulated by different TFs. CONCLUSIONS: Although our data suggest that SOD1 is transcriptionally regulated in response to OS, Nrf2 does not appear to associate with SOD1 promoter in this model of ALS. Our results open new perspectives in the comprehension of two key antioxidant pathways involved in neurodegeneration. Copyright 2015. Published by Elsevier B.V. |
2015
|
Puzzi L; Marchetti L; Peverali FA; Biamonti G; Giacca M DNA-protein interaction dynamics at the Lamin B2 replication origin. Journal Article In: Cell cycle, vol. 14, no. 1, pp. 64-73, 2015. @article{%a1:%Y_357,
title = {DNA-protein interaction dynamics at the Lamin B2 replication origin.},
author = {Puzzi L and Marchetti L and Peverali FA and Biamonti G and Giacca M},
url = {https://www.tandfonline.com/doi/full/10.4161/15384101.2014.973337},
doi = {10.4161/15384101.2014.973337},
year = {2015},
date = {2015-02-05},
journal = {Cell cycle},
volume = {14},
number = {1},
pages = {64-73},
abstract = {To date, a complete understanding of the molecular events leading to DNA replication origin activation in mammalian cells still remains elusive. In this work, we report the results of a high resolution chromatin immunoprecipitation study to detect proteins interacting with the human Lamin B2 replication origin. In addition to the pre-RC component ORC4 and to the transcription factors USF and HOXC13, we found that 2 components of the AP-1 transcription factor, c-Fos and c-Jun, are also associated with the origin DNA during the late G1 phase of the cell cycle and that these factors interact with ORC4. Both DNA replication and AP-1 factor binding to the origin region were perturbed by cell treatment with merbarone, a topoisomerase II inhibitor, suggesting that DNA topology is essential for determining origin function.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
To date, a complete understanding of the molecular events leading to DNA replication origin activation in mammalian cells still remains elusive. In this work, we report the results of a high resolution chromatin immunoprecipitation study to detect proteins interacting with the human Lamin B2 replication origin. In addition to the pre-RC component ORC4 and to the transcription factors USF and HOXC13, we found that 2 components of the AP-1 transcription factor, c-Fos and c-Jun, are also associated with the origin DNA during the late G1 phase of the cell cycle and that these factors interact with ORC4. Both DNA replication and AP-1 factor binding to the origin region were perturbed by cell treatment with merbarone, a topoisomerase II inhibitor, suggesting that DNA topology is essential for determining origin function. |
Arseni L; Lanzafame M; Compe E; Fortugno P; Afonso-Barroso A; Peverali FA; Lehmann AR; Zambruno G; Egly JM; Stefanini M; Orioli D TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin. Journal Article In: Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 5, pp. 1499-1504, 2015. @article{%a1:%Y_409,
title = {TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin.},
author = {Arseni L and Lanzafame M and Compe E and Fortugno P and Afonso-Barroso A and Peverali FA and Lehmann AR and Zambruno G and Egly JM and Stefanini M and Orioli D},
url = {https://www.pnas.org/content/112/5/1499.long},
doi = {10.1073/pnas.1416181112},
year = {2015},
date = {2015-02-03},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {112},
number = {5},
pages = {1499-1504},
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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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. |