UV radiation is acknowledged as the primary cause of photocarcinogenesis and therefore contributes to the development of skin cancer entities such as squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. Typical DNA photoproducts and indirect DNA damage caused by reactive oxygen species are the result of UV radiation. UV-induced DNA damage is repaired by nucleotide excision repair, which consequently counteracts the development of mutations and skin carcinogenesis. Tumour-suppressor genes are inactivated by mutation and growth-promoting pathways are activated leading to disruption of cell-cycle progression. Depending on the skin cancer entity, some genes are more frequently affected than others. In BCC mutations in Patched or Smoothened are common and affect the Sonic hedgehog pathway. In SCC, cell regulator protein p53 (TP53) mutations are prevalent, as well as mutations of the epidermal growth factor receptor (EGFR), cyclin-dependent kinase 2A (CDKN2A), Rat sarcoma (RAS), or the tyrosine kinase Fyn (FYN). UV-induced mutations in TP53 and CDKN2A are frequent in melanoma. UV-induced inflammatory processes also facilitate photocarcinogenesis. Recent studies showed a connection between photocarcinogenesis and citrus consumption, phytochemicals, alcohol consumption, hormone replacement therapy, as well as oral contraceptive use. Preventative measures include adequate use of sun protection and skin cancer screening at regular intervals, as well as the use of chemopreventative agents.

ZusammenfassungDie Nukleotid-Exzisions-Reparatur (NER) ist für die Beseitigung von ultraviolett (UV) -induzierten DNA-Schäden und damit zur Vermeidung von Hautkrebs essenziell. Menschen mit einem genetischen Defekt in der NER, Xeroderma pigmentosum (XP) -Patienten, sind äußerst sonnenempfindlich. Sie entwickeln bereits in den ersten Lebensjahren Zeichen der vorzeitigen Hautalterung mit einem deutlich erhöhten Risiko zur Entwicklung von UV-induzierten kutanen Karzinomen. DNA-Reparaturdefektsyndrome werden vorrangig in der Klinik diagnostiziert und auf molekularer Ebene bestätigt. Für die seltene, rezessiv vererbte Erkrankung XP steht zum jetzigen Zeitpunkt leider noch keine kausale Therapie zur Verfügung, weshalb eine frühe Diagnosestellung umso bedeutsamer ist. Durch frühzeitige sowie konsequente UV-protektive Maßnahmen und eine regelmäßige Überprüfung der Haut im Zuge der Hautkrebsfrüherkennung werden sowohl die Prognose als auch Krankheitsverlauf maßgeblich verbessert.

Ultraviolet (UV)-induced DNA lesions are almost exclusively removed by the nucleotide excision repair (NER) pathway, which is essential for prevention of skin cancer development. Patients with xeroderma pigmentosum (XP) are extremely sun sensitive due to a genetic defect in components of the NER cascade. They present with first signs of premature skin aging at an early age, with a considerably increased risk of developing UV-induced skin cancer. XP belongs to the group of DNA repair defective disorders that are mainly diagnosed in the clinic and in hindsight confirmed at the molecular level. Unfortunately, there are no causative treatment options for this rare, autosomal-recessive disorder, emphasizing the importance of an early diagnosis. Subsequently, UV-protective measures such as the reduction of exposure to environmental UV and regular skin cancer screenings should be undertaken to substantially improve prognosis as well as the disease course.

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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.

Loss-of-function mutations in the synaptosomal-associated protein 29 (SNAP29) lead to the rare autosomal recessive neurocutaneous cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. SNAP29 is a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein. So far, it has been shown to be involved in membrane fusion, epidermal differentiation, formation of primary cilia, and autophagy. Recently, we reported the successful generation of two mouse models for the human CEDNIK syndrome. The aim of this investigation was the generation of a CRISPR/Cas9-mediated SNAP29 knockout (KO) in an immortalized human cell line to further investigate the role of SNAP29 in cellular homeostasis and signaling in humans independently of animal models. Comparison of different methods of delivery for CRISPR/Cas9 plasmids into the cell revealed that lentiviral transduction is more efficient than transfection methods. Here, we reported to the best of our knowledge the first successful generation of a CRISPR/Cas9-mediated SNAP29 KO in immortalized human MRC5Vi fibroblasts (c.169_196delinsTTCGT) via lentiviral transduction.

ZusammenfassungUV-Strahlung gilt als primäre Ursache der Photokarzinogenese und trägt somit zur Entwicklung von kutanen Hautkrebsentitäten wie Plattenepithelkarzinom, Basalzellkarzinom und Melanom bei. Durch UV-Strahlung entstehen einerseits typische DNA-Photoprodukte und andererseits indirekte DNA-Schäden durch reaktive Sauerstoffspezies. UV-bedingte DNA-Schäden werden durch die Nukleotid-Exzisions-Reparatur behoben, die somit der Bildung von Mutationen und der Hautkrebsentwicklung entgegenwirkt. Durch Mutationen werden Tumorsuppressorgene inaktiviert und wachstumsfördernde Signalwege aktiviert, die die normale Zellzyklusprogression stören. Abhängig von der jeweilig zugrunde liegenden Hautkrebsentität, sind bestimmte Gene häufiger betroffen als andere. Basalzellkarzinome weisen häufig Patched- oder Smoothened-Mutationen auf, die den Sonic hedgehog-Signalweg beeinflussen. Plattenepithelkarzinome zeigen vermehrt TP53-Mutationen. Weitere Mutationen umfassen den epidermalen Wachstumsfaktorrezeptor, RAS, FYN und CDKN2A. In Melanomen konnten vor allem UV-induzierte Mutationen in TP53 und CDKN2A nachgewiesen werden. Zudem tragen UV-induzierte Entzündungsprozesse zur Photokarzinogenese bei. Neuere Studien konnten einen Einfluss von Zitrusfruchtkonsum, Alkoholkonsum, Hormonersatztherapien und oralen Kontrazeptiva auf die Photokarzinogenese feststellen. Präventive Maßnahmen gegen UV-bedingte Karzinogenese beinhalten den adäquaten Gebrauch von Sonnenschutz und regelmäßige Hautkrebsvorsorgeuntersuchungen.