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Title: TAT-mediated delivery of a DNA repair enzyme to skin cells rapidly initiates repair of UV-induced DNA damage.

Authors: Johnson, Jodi L; Lowell, Brian C; Ryabinina, Olga P; Lloyd, R Stephen; McCullough, Amanda K

Published In J Invest Dermatol, (2011 Mar)

Abstract: UV light causes DNA damage in skin cells, leading to more than one million cases of non-melanoma skin cancer diagnosed annually in the United States. Although human cells possess a mechanism (nucleotide excision repair) to repair UV-induced DNA damage, mutagenesis still occurs when DNA is replicated before repair of these photoproducts. Although human cells have all the enzymes necessary to complete an alternate repair pathway, base excision repair (BER), they lack a DNA glycosylase that can initiate BER of dipyrimidine photoproducts. Certain prokaryotes and viruses produce pyrimidine dimer-specific DNA glycosylases (pdgs) that initiate BER of cyclobutane pyrimidine dimers (CPDs), the predominant UV-induced lesions. Such a pdg was identified in the Chlorella virus PBCV-1 and termed Cv-pdg. The Cv-pdg protein was engineered to contain a nuclear localization sequence (NLS) and a membrane permeabilization peptide (transcriptional transactivator, TAT). Here, we demonstrate that the Cv-pdg-NLS-TAT protein was delivered to repair-proficient keratinocytes and fibroblasts, and to a human skin model, where it rapidly initiated removal of CPDs. These data suggest a potential strategy for prevention of human skin cancer.

PubMed ID: 20927123 Exiting the NIEHS site

MeSH Terms: Administration, Topical; Cell Line; Cell Nucleus/metabolism; Chlorella*; DNA Damage/drug effects; DNA Damage/radiation effects*; DNA Glycosylases/administration & dosage; DNA Glycosylases/pharmacology*; DNA Repair/drug effects*; DNA/metabolism; Fibroblasts/cytology; Fibroblasts/drug effects; Fibroblasts/metabolism; Humans; Keratinocytes/cytology; Keratinocytes/drug effects; Keratinocytes/metabolism; Pyrimidine Dimers/metabolism; Skin Neoplasms/prevention & control; Skin/cytology; Skin/drug effects*; Skin/metabolism; Ultraviolet Rays/adverse effects*

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