1,720,975 research outputs found
Photocarcinogenesis and Skin Cancer Prevention Strategies
No full textIn this review the basic principles of UV-induced carcinogenesis are summarized and the state of the art diagnosis and therapeutic strategies are discussed. The prevalent keratinocyte-derived neoplasms of the skin are basal cell and squamous cell carcinomas. Cutaneous melanoma is less frequent but associated with high mortality. Common risk factors for all three tumor entities include sun exposure and DNA-repair deficiencies. Photocarcinogenesis follows a multistep model of cancer development in which ultraviolet-induced DNA damage leads to mutations resulting in activation of oncogenes or silencing of tumor-suppressor genes. This ends in a cellular mutator phenotype even more prone to mutation acquisition. DNA repair, especially the nucleotide excision repair (NER) pathway, counteracts mutation formation and skin cancer development. This is vividly demonstrated by the NER-defective disorder xeroderma pigmentosum. Primary skin cancer preventative strategies, therefore, include reduction of DNA photodamage by protection from the sun. Secondary preventative strategies include skin cancer screening. This implies standard examination techniques with the naked eye, an epiluminescence microscope, or digital epiluminescence microscopy. More advanced techniques include confocal laser scan microscopy
Photocarcinogenesis and Skin Cancer Prevention Strategies
No full textIn this review the basic principles of UV-induced carcinogenesis are summarized and the state of the art diagnosis and therapeutic strategies are discussed. The prevalent keratinocyte-derived neoplasms of the skin are basal cell and squamous cell carcinomas. Cutaneous melanoma is less frequent but associated with high mortality. Common risk factors for all three tumor entities include sun exposure and DNA-repair deficiencies. Photocarcinogenesis follows a multistep model of cancer development in which ultraviolet-induced DNA damage leads to mutations resulting in activation of oncogenes or silencing of tumor-suppressor genes. This ends in a cellular mutator phenotype even more prone to mutation acquisition. DNA repair, especially the nucleotide excision repair (NER) pathway, counteracts mutation formation and skin cancer development. This is vividly demonstrated by the NER-defective disorder xeroderma pigmentosum. Primary skin cancer preventative strategies, therefore, include reduction of DNA photodamage by protection from the sun. Secondary preventative strategies include skin cancer screening. This implies standard examination techniques with the naked eye, an epiluminescence microscope, or digital epiluminescence microscopy. More advanced techniques include confocal laser scan microscopy
XPF knockout via CRISPR/Cas9 reveals that ERCC1 is retained in the cytoplasm without its heterodimer partner XPF
No full textThe XPF/ERCC1 heterodimeric complex is essentially involved in nucleotide excision repair (NER), interstrand crosslink (ICL), and double-strand break repair. Defects in XPF lead to severe diseases like xeroderma pigmentosum (XP). Up until now, XP-F patient cells have been utilized for functional analyses. Due to the multiple roles of the XPF/ERCC1 complex, these patient cells retain at least one full-length allele and residual repair capabilities. Despite the essential function of the XPF/ERCC1 complex for the human organism, we successfully generated a viable immortalised human XPF knockout cell line with complete loss of XPF using the CRISPR/Cas9 technique in fetal lung fibroblasts (MRC5Vi cells). These cells showed a markedly increased sensitivity to UVC, cisplatin, and psoralen activated by UVA as well as reduced repair capabilities for NER and ICL repair as assessed by reporter gene assays. Using the newly generated knockout cells, we could show that human XPF is markedly involved in homologous recombination repair (HRR) but dispensable for non-homologous end-joining (NHEJ). Notably, ERCC1 was not detectable in the nucleus of the XPF knockout cells indicating the necessity of a functional XPF/ERCC1 heterodimer to allow ERCC1 to enter the nucleus. Overexpression of wild-type XPF could reverse this effect as well as the repair deficiencies
Functional characterization of XPG and its spontaneous splice variants during nucleotide excision repair
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Palmoplantar dermatoses. When should genes be considered?
No full textPalmoplantar dermatoses are common. They can be both functionally debilitating and markedly stigmatize the patient because they are so visible. Dermatoses on the hands and feet often go along with palmoplantar hyperkeratosis. Such palmoplantar keratoses (PPK) can be classified into acquired (non-hereditary) and hereditary (monogenetic) PPK. A considerable proportion of PPK develop on the grounds of gene defects. As these diseases constitute a heterogeneous group of quite uncommon single entities, the treating physician must know when to entertain the diagnosis of a hereditary PPK and which causative genes should be considered. We summarize the common causes of acquired and hereditary PPK based on a review of the latest literature. The most common causes of acquired PPK are inflammatory dermatoses like psoriasis, lichen planus, or hand and feet eczema. Also irritative-toxic (arsenic poisoning, polycyclic aromatic hydrocarbons) and infectious causes of PPK (human papilloma viruses, syphilis, scabies, tuberculosis, mycoses) are not uncommon. Genetically caused PPK may occur isolated, within syndromes or as a paraneoplastic marker. The clinical/histological classification discerns diffuse, focal, or punctuate forms of PPK with and without epidermolysis. A new classification based on the causative gene defect is starting to replace the traditional clinical classification. Knowledge about the large, but heterogeneous group of hereditary PPK is important to adequately counsel and treat patients and their families
Functional characterization of XPG and its spontaneous splice variants during nucleotide excision repair
No full textFunctional relevance of spontaneous alternative splice variants of the xeroderma pigmentosum group F gene
No full textFunctional relevance of spontaneous alternative splice variants of the xeroderma pigmentosum group F gene
No full textA unique chromosomal in-frame deletion identified among seven XP-C patients
No full textBackgroundThe nucleotide excision repair (NER) pathway, defective in xeroderma pigmentosum (XP) patients, removes DNA photolesions in order to prevent carcinogenesis. Complementation group C (XP-C) is the most frequent group of XP patients worldwide. MethodsWe analyzed seven XP-C patients clinically and molecular-genetically applying: post-UV cell survival (MTT-assay), quantitative Real-time PCR, sequencing on chromosomal as well as cDNA level, and in silico interpretation of sequencing data. ResultsAll cases displayed diminished post-UV cell survival as well as reduced XPCmRNA levels. Five homozygous and two heterozygous disease causing mutations were identified. A large chromosomal deletion of similar to 5.8 kb identified in XP174MA leads to an unique in frame deletion of XPC exon 2 and exon 3. In silico analysis revealed the deletion of 102 amino acids in the N-terminal part of XPC while leaving the C-terminal domain intact. The novel c.361delA mutation in XP168MA leads to a frameshift in exon 3 resulting in a premature stop codon 27 codons downstream of the deleted adenine. ConclusionOur analysis confirms that XP-C patients without increased sun sensitivity develop non-melanoma skin cancers earlier than sun-sensitive XP-C patients. Reduced cellular mRNA levels are characteristic for XP complementation group C and qRT-PCR represents a rapid diagnostic tool
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