Topical Application of Preparations Containing DNA Repair Enzymes Prevents Ultraviolet-Induced Telomere Shortening and c-FOS Proto-Oncogene Hyperexpression in Human Skin: An Experimental Pilot Study

September 2013 | Volume 12 | Issue 9 | Original Article | 1017 | Copyright © 2013

Enzo Emanuele MD,a Velimir Altabas MD,b Karmela Altabas MD,b and Enzo Berardesca MDc

aDepartment of Health Sciences, University of Pavia, Pavia, Italy
bClinical Hospital “Sestre Milosrdnice”, Zagreb, Croatia
cSan Gallicano Dermatological Institute, Rome, Italy

Abstract

The exposure to ultraviolet radiation (UVR) is one of the most important risk factors for skin aging and increases the risk of malignant transformation. Telomere shortening and an altered expression of the proto-oncogene c-FOS are among the key molecular mechanisms associated with photoaging and tumorigenesis. Photolyase from A. nidulans and endonuclease from M. luteus are xenogenic DNA repair enzymes which can reverse the molecular events associated with skin aging and carcinogenosis caused by UVR exposure. Therefore, the purpose of this study was to investigate whether the topical application of preparations containing DNA repair enzymes may prevent UVR-induced acute telomere shortening and FOS gene hyperexpression in human skin biopsies. Twelve volunteers (Fitzpatrick skin types I and II) were enrolled for this experimental study, and six circular areas (10 mm diameter) were marked out on the nonexposed lower back of each participant. One site was left untreated (site 1: negative control), whereas the remaining five sites (designated sites 2–6) were exposed to solar-simulated UVR at 3 times the MED on four consecutive days. Site 2 received UVR only (site 2: positive control), whereas the following products were applied to sites 3–6, respectively: vehicle (moisturizer base cream; applied both 30 minutes before and immediately after each irradiation; site 3); a traditional sunscreen (SS, SPF 50) 30 minutes before irradiation and a vehicle immediately after irradiation (site 4); a SS 30 minutes before irradiation and an endonuclease preparation immediately after irradiation (site 5); a SS plus photolyase 30 minutes before irradiation and an endonuclease preparation immediately after irradiation (site 6). Skin biopsies were taken 24 h after the last irradiation. The degree of telomere shortening and c-FOS gene expression were measured in all specimens. Strikingly, the combined use of a SS plus photolyase 30 minutes before irradiation and an endonuclease preparation immediately after irradiation completely abrogated telomere shortening and c-FOS gene hyperexpression induced by the experimental irradiations. We conclude that the topical application of preparations containing both photolyase from A. nidulans and endonuclease from M. luteus may be clinically useful to prevent skin aging and carcinogenesis by abrogating UVR-induced telomere shortening and c-FOS gene hyperexpression.

J Drugs Dermatol. 2013;12(9):1017-1021.

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INTRODUCTION

Chronic excessive exposure to ultraviolet radiation (UVR) from sunlight is a causative factor in the development of photoaging and skin malignancies.1-3 The harmful effects of UVR from sunlight is currently considered the major environmental risk factor for skin cancer and a complete carcinogen by damaging DNA4 and suppressing immune responses.5 The increased risk of cutaneous malignancies linked to chronic UVR exposure has been associated with direct DNA damage,6 which is mainly represented by the formation of cyclobutane pyrimidine dimers (CPD) that result from the photo [2 + 2] cycloaddition of the 5,6-double bond of two adjacent pyrimidine nucleotides.7,8

Photolyase from A. nidulans9,10 and endonuclease from M. luteus11,12 are xenogenic DNA repair enzymes which can reverse the molecular events associated with skin aging and carcinogenosis caused by UVR exposure. In this regard, previous studies have shown that topical treatments utilizing photolyase and/or endonuclease in liposomal lotions may prove effective in reducing the risk of skin cancer in patients with defective DNA repair or in other at-risk patient populations by reverting the genome-damaging effects caused by UVR.9,10,13,14 Photolyases comprise efficient enzymes to remove the major UV-induced DNA lesion, ie, CPD.15 The catalytic action of photolyase employs the light-driven injection of an electron onto the DNA lesion to trigger the cleavage of CPD.15 Similarly, endonuclease from M. luteus acts as a CPD glycosylase/abasic lyase but – differently from photolyse – does not require light energy activation.12

Evidence suggests that specific molecular derangements – including telomere shortening16-19 and the upregulation of proto-oncogenes20,21 – may play a role in the setting of UVR-induced damage to biological tissues. Telomeres are specialized DNA, made up of a string of repeated TTAGGG located in the end of the chromosomes.22 They protect the ends of the chromosomes from

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