Modulation of UVB-induced Carcinogenesis by Activation of Alternative DNA Repair Pathways

• Type of Material: Article
• Authors: Yan Sha, Oregon Health & Science University; Vladimir Vartanian, Oregon Health & Science University; Nichole Owen, Oregon Health & Science University; Stephanie J. Mengden Koon, Oregon Health & Science University; Marcus J. Calkins, Oregon Health & Science University; Courtney S. Thompson, Encapsula NanoSciences; Zahra Mirafzali, Encapsula NanoSciences; Sara Mir, Encapsula NanoSciences; Lisa E. Goldsmith, Accelagen Incorporated; Huaping He, Accelagen Incorporated; Chun Luo, Accelagen Incorporated; Scott M. Brown, Brown Hale Consulting, Inc; Paul Doetsch, Emory University; Andy Kaempf, Oregon Health & Science University; Jeong Y. Lim, Oregon Health & Science University; Amanda K. McCullough, Oregon Health & Science University; R. Stephen Lloyd, Oregon Health & Science University
• Language: English
• Date: 2018-01-15
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-017-17940-8
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 8
• Issue: 1
• Start Page: 705
• End Page: 705
• Grant/Funding Information: MJC was supported by the Training Program in the Molecular Basis of Skin/Mucosa Pathobiology (T32-CA106195).; YS was supported by China Scholarship Fund (No.201508440020).; This work was partially funded by NIH R01 ES04091, R41 and R42 ES021623.
• Keywords: SKIN-CANCER; BACTERIOPHAGE-T4; MAMMALIAN-CELLS; Multidisciplinary Sciences; LIPOSOMES; TRANSCRIPTION-COUPLED REPAIR; Science & Technology - Other Topics; CYCLOBUTANE PYRIMIDINE DIMERS; Science & Technology; IN-VITRO; DAMAGE ENDONUCLEASE; XERODERMA-PIGMENTOSUM; SCHIZOSACCHAROMYCES-POMBE
• Research Categories: Biology, Genetics; Biology, Molecular

Abstract

The molecular basis for ultraviolet (UV) light-induced nonmelanoma and melanoma skin cancers centers on cumulative genomic instability caused by inefficient DNA repair of dipyrimidine photoproducts. Inefficient DNA repair and subsequent translesion replication past these DNA lesions generate distinct molecular signatures of tandem CC to TT and C to T transitions at dipyrimidine sites. Since previous efforts to develop experimental strategies to enhance the repair capacity of basal keratinocytes have been limited, we have engineered the N-terminally truncated form (Δ228) UV endonuclease (UVDE) from Schizosaccharomyces pombe to include a TAT cell-penetrating peptide sequence with or without a nuclear localization signal (NLS): UVDE-TAT and UVDE-NLS-TAT. Further, a NLS was engineered onto a pyrimidine dimer glycosylase from Paramecium bursaria chlorella virus-1 (cv-pdg-NLS). Purified enzymes were encapsulated into liposomes and topically delivered to the dorsal surface of SKH1 hairless mice in a UVB-induced carcinogenesis study. Total tumor burden was significantly reduced in mice receiving either UVDE-TAT or UVDE-NLS-TAT versus control empty liposomes and time to death was significantly reduced with the UVDE-NLS-TAT. These data suggest that efficient delivery of exogenous enzymes for the initiation of repair of UVB-induced DNA damage may protect from UVB induction of squamous and basal cell carcinomas.