Isoconazole and Clemizole Hydrochloride Partially Reverse the Xeroderma Pigmentosum C Phenotype

Xeroderma Pigmentosum protein C (XPC) is involved in recognition and repair of bulky DNA damage such as lesions induced by Ultra Violet (UV) radiation. XPC-mutated cells are, therefore, photosensitive and accumulate UVB-induced pyrimidine dimers leading to increased cancer incidence. Here, we performed a high-throughput screen to identify chemicals capable of normalizing the XP-C phenotype (hyper-photosensitivity and accumulation of photoproducts). Fibroblasts from XP-C patients were treated with a library of approved chemical drugs. Out of 1280 tested chemicals, 16 showed ≥25% photo-resistance with RZscore above 2.6 and two drugs were able to favor repair of 6-4 pyrimidine pyrimidone photoproducts (6-4PP). Among these two compounds, Isoconazole could partially inhibit apoptosis of the irradiated cells especially when cells were post-treated directly after UV irradiation while Clemizole Hydrochloride-mediated increase in viability was dependent on both pre and post treatment. No synergistic effect was recorded following combined drug treatment and the compounds exerted no effect on the proliferative capacity of the cells post UV exposure. Amelioration of XP-C phenotype is a pave way towards understanding the accelerated skin cancer initiation in XP-C patients. Further examination is required to decipher the molecular mechanisms targeted by these two chemicals.

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Isoconazole and Clemizole Hydrochloride Partially Reverse the Xeroderma Pigmentosum C Phenotype

10.21203/rs.3.rs-197694/v1 ◽

2021 ◽

Author(s):

Farah Kobaisi ◽

Eric Sulpice ◽

Caroline Barette ◽

Nour Fayyad ◽

Marie-Odile Fauvarque ◽

...

Keyword(s):

Dna Damage ◽

Skin Cancer ◽

Synergistic Effect ◽

Xeroderma Pigmentosum ◽

Protein C ◽

Molecular Mechanisms ◽

Ultra Violet ◽

Uv Exposure ◽

Proliferative Capacity ◽

Cancer Initiation

Abstract Xeroderma Pigmentosum protein C (XPC) is involved in recognition and repair of bulky DNA damage such as lesions induced by Ultra Violet (UV) radiation. XPC-mutated cells are, therefore, photosensitive and accumulate DNA damage leading to increased cancer incidence. Here, we performed a high-throughput screen to identify chemicals capable of normalizing the XP-C phenotype (hyper-photosensitivity and accumulation of photoproducts). Fibroblasts from XP-C patients were treated with a library of approved chemical drugs. Out of 1280 tested chemicals, 16 showed ≥ 25% photo-resistance with RZscore above 2.6 and two drugs were able to favor repair of 6 − 4 pyrimidine pyrimidone photoproducts (6-4PP). Among these two compounds, Isoconazole could partially inhibit apoptosis of the irradiated cells especially when cells were post-treated directly after UV irradiation while Clemizole Hydrochloride-mediated increase in viability was dependent on both pre and post-treatment. No synergistic effect was recorded following combined drug treatment and the compounds exerted no effect on the proliferative capacity of the cells post UV exposure. Amelioration of XP-C phenotype is a pave way towards understanding the accelerated skin cancer initiation in XP-C patients. Further examination is required to decipher the molecular mechanisms targeted by these two chemicals.

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Skin Cancer

10.1093/oso/9780190676827.003.0015 ◽

2018 ◽

Cited By ~ 1

Author(s):

Adèle C. Green ◽

Catherine M. Olsen ◽

David J. Hunter

Keyword(s):

Skin Cancer ◽

Cell Carcinoma ◽

Uv Radiation ◽

Molecular Mechanisms ◽

Sun Exposure ◽

Uv Exposure ◽

Skin Cancers ◽

Cells Of Origin ◽

Solar Ultraviolet

Skin cancer is one of the few types of cancer for which exposure to the major carcinogen, solar ultraviolet (UV) radiation, is strongly implicated on the basis of descriptive epidemiologic data alone. There are three major forms of skin cancer considered in this chapter—melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC)—and each appears to have different causal relations to the pattern and total amount of sun exposure. High-intensity UV exposure and long-term UV exposure appear to be involved differentially in the various skin cancers and their subtypes. Underlying molecular mechanisms are becoming better understood, though many aspects like the cells of origin and the exact roles of intermediate lesions like actinic keratoses and nevi remain unclear. Because exposure of skin to UV radiation is modifiable, skin cancers are substantially preventable.

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Xeroderma Pigmentosum: Gene Variants and Splice Variants

Genes ◽

10.3390/genes12081173 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1173

Author(s):

Marie Christine Martens ◽

Steffen Emmert ◽

Lars Boeckmann

Keyword(s):

Dna Damage ◽

Xeroderma Pigmentosum ◽

Splice Variants ◽

Excision Repair ◽

Genetic Disorder ◽

Cyclobutane Pyrimidine Dimers ◽

Pyrimidine Dimers ◽

Damage Repair ◽

Nucleotide Excision ◽

Functional Relevance

The nucleotide excision repair (NER) is essential for the repair of ultraviolet (UV)-induced DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and 6,4-pyrimidine-pyrimidone dimers (6,4-PPs). Alterations in genes of the NER can lead to DNA damage repair disorders such as Xeroderma pigmentosum (XP). XP is a rare autosomal recessive genetic disorder associated with UV-sensitivity and early onset of skin cancer. Recently, extensive research has been conducted on the functional relevance of splice variants and their relation to cancer. Here, we focus on the functional relevance of alternative splice variants of XP genes.

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An Xpb Mouse Model for Combined Xeroderma Pigmentosum and Cockayne Syndrome Reveals Progeroid Features upon Further Attenuation of DNA Repair

Molecular and Cellular Biology ◽

10.1128/mcb.01229-08 ◽

2008 ◽

Vol 29 (5) ◽

pp. 1276-1290 ◽

Cited By ~ 39

Author(s):

Jaan-Olle Andressoo ◽

Geert Weeda ◽

Jan de Wit ◽

James R. Mitchell ◽

Rudolf B. Beems ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Xeroderma Pigmentosum ◽

Molecular Mechanisms ◽

Excision Repair ◽

Cockayne Syndrome ◽

Repair Capacity ◽

Dna Repair Capacity ◽

Neonatal Lethality ◽

Nucleotide Excision

ABSTRACT Patients carrying mutations in the XPB helicase subunit of the basal transcription and nucleotide excision repair (NER) factor TFIIH display the combined cancer and developmental-progeroid disorder xeroderma pigmentosum/Cockayne syndrome (XPCS). Due to the dual transcription repair role of XPB and the absence of animal models, the underlying molecular mechanisms of XPBXPCS are largely uncharacterized. Here we show that severe alterations in Xpb cause embryonic lethality and that knock-in mice closely mimicking an XPCS patient-derived XPB mutation recapitulate the UV sensitivity typical for XP but fail to show overt CS features unless the DNA repair capacity is further challenged by crossings to the NER-deficient Xpa background. Interestingly, the Xpb XPCS Xpa double mutants display a remarkable interanimal variance, which points to stochastic DNA damage accumulation as an important determinant of clinical diversity in NER syndromes. Furthermore, mice carrying the Xpb XPCS mutation together with a point mutation in the second TFIIH helicase Xpd are healthy at birth but display neonatal lethality, indicating that transcription efficiency is sufficient to permit embryonal development even when both TFIIH helicases are crippled. The double-mutant cells exhibit sensitivity to oxidative stress, suggesting a role for endogenous DNA damage in the onset of XPB-associated CS.

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Light or Dark Pigmentation of Engineered Skin Substitutes Containing Melanocytes Protects Against Ultraviolet Light-Induced DNA Damage In Vivo

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa029 ◽

2020 ◽

Vol 41 (4) ◽

pp. 751-760

Author(s):

Dorothy M Supp ◽

Jennifer M Hahn ◽

Christopher M Lloyd ◽

Kelly A Combs ◽

Viki B Swope ◽

...

Keyword(s):

Dna Damage ◽

Skin Cancer ◽

Human Skin ◽

Skin Substitutes ◽

Normal Human Skin ◽

Immunodeficient Mice ◽

Pyrimidine Dimers ◽

Dark Pigmentation ◽

Engineered Skin Substitutes

Abstract Engineered skin substitutes (ESS) containing autologous fibroblasts and keratinocytes provide stable wound closure in patients with large, full-thickness burns, but are limited by hypopigmentation due to absence of added melanocytes. DNA damage caused by ultraviolet radiation (UV) increases risk for skin cancer development. In human skin, melanocytes provide pigmentation that protects skin from UV-induced DNA damage. This study investigated whether inclusion of human melanocytes (hM) affects the response of ESS to UV in vivo. Specifically, pigmentation and formation of cyclobutane pyrimidine dimers (CPDs), the most prevalent UV-induced DNA photoproduct, were analyzed. Three groups of ESS were prepared with fibroblasts and keratinocytes, ± melanocytes, and grafted orthotopically to immunodeficient mice: ESS without melanocytes (ESS-hM), ESS with light skin-derived (Caucasian) melanocytes (ESS+hM-L), and ESS with dark skin-derived (African-American) melanocytes (ESS+hM-D). Pigmentation of ESS+hM-L and ESS+hM-D increased significantly after grafting; pigmentation levels were significantly different among groups. Mean melanocyte densities in ESS+hM-L and ESS+hM-D were similar to each other and to densities in normal human skin. After 8 weeks in vivo, grafts were irradiated with 135 mJ/cm2 UV; non-UV-treated mice served as controls. UV modestly increased pigmentation in the ESS+hM groups. UV significantly increased CPD levels in ESS-hM, and levels in ESS-hM were significantly greater than in ESS+hM-L or ESS+hM-D. The results demonstrate that light or dark melanocytes in ESS decreased UV-induced DNA damage. Therefore, melanocytes in ESS play a photoprotective role. Protection against UV-induced DNA damage is expected to reduce skin cancer risk in patients grafted with ESS containing autologous melanocytes.

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