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

Yan Sha, Vladimir Vartanian, Nichole Owen, Stephanie J. Mengden Koon, Marcus J. Calkins, Courtney S. Thompson, Zahra Mirafzali, Sara Mir, Lisa E. Goldsmith, Huaping He, Chun Luo, Scott M. Brown, Paul W. Doetsch, Andy Kaempf, Jeong Y. Lim, Amanda McCullough, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Article number705
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Modulation of UVB-induced Carcinogenesis by Activation of Alternative DNA Repair Pathways'. Together they form a unique fingerprint.

  • Cite this

    Sha, Y., Vartanian, V., Owen, N., Mengden Koon, S. J., Calkins, M. J., Thompson, C. S., Mirafzali, Z., Mir, S., Goldsmith, L. E., He, H., Luo, C., Brown, S. M., Doetsch, P. W., Kaempf, A., Lim, J. Y., McCullough, A., & Lloyd, R. S. (2018). Modulation of UVB-induced Carcinogenesis by Activation of Alternative DNA Repair Pathways. Scientific Reports, 8(1), [705]. https://doi.org/10.1038/s41598-017-17940-8