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1.
Front Genet ; 11: 561687, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329698

RESUMO

Xeroderma Pigmentosum C (XPC) is a multi-functional protein that is involved not only in the repair of bulky lesions, post-irradiation, via nucleotide excision repair (NER) per se but also in oxidative DNA damage mending. Since base excision repair (BER) is the primary regulator of oxidative DNA damage, we characterized, post-Ultraviolet B-rays (UVB)-irradiation, the detailed effect of three different XPC mutations in primary fibroblasts derived from XP-C patients on mRNA, protein expression and activity of different BER factors. We found that XP-C fibroblasts are characterized by downregulated expression of different BER factors including OGG1, MYH, APE1, LIG3, XRCC1, and Polß. Such a downregulation was also observed at OGG1, MYH, and APE1 protein levels. This was accompanied with an increase in DNA oxidative lesions, as evidenced by 8-oxoguanine levels, immediately post-UVB-irradiation. Unlike in normal control cells, these oxidative lesions persisted over time in XP-C cells having lower excision repair capacities. Taken together, our results indicated that an impaired BER pathway in XP-C fibroblasts leads to longer persistence and delayed repair of oxidative DNA damage. This might explain the diverse clinical phenotypes in XP-C patients suffering from cancer in both photo-protected and photo-exposed areas. Therapeutic strategies based on reinforcement of BER pathway might therefore represent an innovative path for limiting the drawbacks of NER-based diseases, as in XP-C case.

2.
Oncogenesis ; 8(10): 52, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551419

RESUMO

The leading cause of cutaneous squamous cell carcinomas (cSCCs) is exposure to ultraviolet radiation (UV). Unlike most other cancers, the incidence rates of cSCCs are still on the rise and the treatment options currently available are limited. We have recently found that dihydroorotate dehydrogenase (DHODH), which is the rate-limiting enzyme in the de novo pyrimidine synthesis pathway, plays a critical role in UVB-induced energy metabolism reprogramming. Using a multistage model of UVB radiation-induced skin cancer, we show that UVB-induced DHODH upregulation is mainly regulated transcriptionally by STAT3. Our results indicate that chronic inhibition of DHODH by leflunomide (LFN) blocks UVB-induced tumor initiation. Human tumor xenograft studies showed that LFN treatment reduces growth of established tumors when used in combination with a genotoxic agent, 5-fluorouracil (5-FU). Our data suggest that DHODH is a promising target for chemoprevention and combination therapy of UVB-induced cSCCs.

3.
Eur J Hum Genet ; 25(1): 52-58, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-27759030

RESUMO

The ubiquitin-proteasome pathway is involved in the pathogenesis of several neurogenetic diseases. We describe a Mauritanian patient harboring a homozygous deletion restricted to two contiguous genes HERC2 and OCA2 and presenting with severe developmental abnormalities. The deletion causes the complete loss of HERC2 protein function, an E3-ubiquitin ligase. HERC2 is known to target XPA and BRCA1 for degradation and a mechanism whereby it is involved in DNA repair and cell cycle regulation. We showed that loss of HERC2 function leads to the accumulation of XPA and BRCA1 in the patient's fibroblasts and generates decreased sensitivity to apoptosis and increased level of DNA repair. Our data describe for the first time the phenotypic consequences, both at the clinical and cellular levels, of a complete loss of HERC2 function in a patient. They strongly suggest that profound ubiquitin ligase - associated dysfunction is responsible for the severe phenotype in this patient, and that dysfunction of this pathway may be involved in other patients with similar neurodevelopmental diseases.


Assuntos
Proteína BRCA1/genética , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Transtornos do Neurodesenvolvimento/genética , Proteína de Xeroderma Pigmentoso Grupo A/genética , Ciclo Celular/genética , Hibridização Genômica Comparativa , Reparo do DNA/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Deleção de Genes , Homozigoto , Humanos , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Ubiquitina-Proteína Ligases
5.
J Invest Dermatol ; 135(2): 341-351, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25296907

RESUMO

Nucleotide excision repair (NER) is an important DNA repair pathway involved in the removal of a wide array of DNA lesions. The absence or dysfunction of NER results in the following distinct disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS), cerebro-oculo-facio-skeletal (COFS) syndrome, UV-sensitive syndrome (UVSS), trichothiodystrophy (TTD), or combined syndromes including XP/CS, XP/TTD, CS/TTD, and COFS/TTD. In addition to their well-characterized role in the NER signaling pathway, NER factors also seem to be important in biological processes that are not directly associated with DNA damage responses, including mitochondrial function and redox homeostasis. The potential causative role of these factors in the large clinical spectrum seen in NER diseases is discussed in this review.


Assuntos
Reparo do DNA , Metabolismo Energético , Antioxidantes/uso terapêutico , Síndrome de Cockayne/genética , Síndrome de Cockayne/metabolismo , Humanos , Oxirredução , Transtornos de Fotossensibilidade/genética , Transtornos de Fotossensibilidade/metabolismo , Síndromes de Tricotiodistrofia/genética , Síndromes de Tricotiodistrofia/metabolismo , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/metabolismo
6.
J Invest Dermatol ; 131(9): 1793-805, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21633368

RESUMO

Besides lung, postnatal human epidermis is the only epithelium in direct contact with atmospheric oxygen. Skin epidermal oxygenation occurs mostly through atmospheric oxygen rather than tissue vasculature, resulting in a mildly hypoxic microenvironment that favors increased expression of hypoxia-inducible factor-1α (HIF-1α). Considering the wide spectrum of biological processes, such as angiogenesis, inflammation, bioenergetics, proliferation, motility, and apoptosis, that are regulated by this transcription factor, its high expression level in the epidermis might be important to HIF-1α in skin physiology and pathophysiology. Here, we review the role of HIF-1α in cutaneous angiogenesis, skin tumorigenesis, and several skin disorders.


Assuntos
Carcinoma de Células Escamosas/fisiopatologia , Epiderme/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Neovascularização Fisiológica/fisiologia , Neoplasias Cutâneas/fisiopatologia , Carcinoma de Células Escamosas/metabolismo , Humanos , Oxigênio/metabolismo , Dermatopatias/metabolismo , Dermatopatias/fisiopatologia , Neoplasias Cutâneas/metabolismo
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