1136 Xeroderma Pigmentosum: From disease modeling using CRISPR-Cas9 technology to the understanding of skin cancers pathophysiology
نویسندگان
چکیده
The sun's DNA-damaging ultraviolet (UV) radiation remains the major extrinsic risk factor for skin cancer development. Nevertheless, mammalian cells exploit presence of nucleotide excision repair (NER) pathway as a protective shield to eliminate accumulation photoproducts triggered by UV radiation. Xeroderma Pigmentosum C (XPC) is key multifunctional protein implicated in NER acting sensor DNA lesions. Loss-of-function mutations theXPC gene confer photosensitive phenotype with buildup damage without XPC patients' and will tend increase 10,000 folds onset. To date, there no relevant reproducible cellular model that can mimic course human disease. We carried out, first time, XPCgene editing several (keratinocytes, fibroblasts, melanocytes) using CRISPR-Cas9 technology. Following disease characterization, WT knockout models were used map proteomic signature KO at basal state its modifications post irradiation. For this, total proteomes subjected or not irradiation analysed mass spectrometry-based quantitative proteomics. Surprisingly, unique 400 proteins was significantly (p=0.01, FDR 1%) differentially altered irradiated versus cells. better decipher signaling pathways implicated, kinases phosphorylation activity also quantified post-UV bioinformatic analysis all significant data, we identified complete dysregulation JAK/STAT from upstream downstream effectors. well-known inflammatory pathway, thus blocking it might be treasure alleviate
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ژورنال
عنوان ژورنال: Journal of Investigative Dermatology
سال: 2023
ISSN: ['1523-1747', '0022-202X']
DOI: https://doi.org/10.1016/j.jid.2023.03.1149