J. Cosmet. Sci., 71, 209–214 (July/August 2020) 209 Importance of DNA Repair: Recent Advances DANIEL B. YAROSH and ANGELA TEWARI , Daniel B. Yarosh, Inc., Merrick, NY (D.B.Y.), Department of Dermatology, Kings College Hospital, NHS Foundation Trust, London SEI 9RT, United Kingdom (A.T.) Synopsis Our defense against solar ultraviolet (UV) damage to skin comprises endogenous mechanisms of DNA repair and pigmentation, and exogenous application of light-absorbing and refl ecting sunscreens. Our most important endogenous defense, DNA repair, has been the focus of molecular and clinical research, and recent advances are summarized here. The approach of using microbial DNA repair enzymes to augment the natural DNA repair capacity of skin has gained acceptance in many commercial products, and clinical studies have supported their benefi ts. INTRODUCTION DNA repair is the most important endogenous protection against sunlight damage to skin. A defi ciency in DNA repair causes the genetic disease xeroderma pigmentosum (XP) classic form, wherein one of seven genes is disabled by mutation, resulting in extreme sun sensitivity, skin cancer, and premature death (1). The symptoms of XP are as severe in people of color as in light-skinned patients, demonstrating that effi cient DNA repair capacity is more important in providing protection from ultraviolet (UV)-induced pre- cancerous cutaneous changes than is melanin pigmentation (1). Even the heavy melanin content of black skin affords a protection of only 20- to 60-fold against skin cancer (2), whereas XP patients younger than 20 years have a 10,000-fold increased risk of non- melanoma skin cancer and a 2,000-fold increased risk of melanoma (1). Chemical and physical sunscreens are the most important exogenous systems of photo- protection. Despite their intrinsic ability to block DNA damage (3), sunscreens are often used at a fraction of the recommended application dose (4). The potential for systemic absorption and environmental damage (5) has led to a search for alternatives, and increas- ing the endogenous DNA repair system is an attractive goal. Here, we will highlight recent advances in understanding DNA repair protection against solar radiation and review the support for the use of exogenous DNA repair enzymes for photoprotection. Address all correspondence to Daniel B. Yarosh at dyarosh@danyarosh.com.

JOURNAL OF COSMETIC SCIENCE 210 DNA DAMAGE Sunlight, primarily the shorter wavelengths in the UV range, are absorbed by the DNA in living skin cells, producing a variety of direct chemical modifi cations as well as modi- fi cations by reactive molecules secondarily produced by sunlight (recently reviewed in ref. 6). The most common form is the cyclobutane pyrimidine dimer (CPD, fusion of adjacent DNA bases) followed by the (6-4) photoproduct (6-4PP, also a fusion of DNA bases) and oxidation of the DNA base guanine producing 8-oxo-guanine (8oGua). On a macroscopic level, the occurrence of CPDs is randomly distributed along the genome at dipyrimidine sites, but closer examination has revealed that nucleosomes infl uence DNA damage for- mation and repair (7), and hotspots adjacent to certain transcription-binding sites prefer- entially accumulate DNA damage.(8) Telomeres, the special tips of chromosomes, are especially susceptible to damage due to the high density of dipyrimidines (9). Long wave ultraviolet A (UVA) (UVA1 340–400 nm) produces CPD with a predilection for the basal epidermis where the actively dividing stem cells reside, and thus broad band photopro- tection is important for reducing the DNA damage burden (10) . The predominant mutation in keratinocyte tumors is the ultraviolet radiation (UVR) signature mutation (11,12), and the CPD is of particular trepidation for skin health, as not only does its formation triggers erythema and the sunburn reaction (13) but also immune suppression that allows the outgrowth of skin tumors (14). Sunscreens are less effi cient in preventing immunosuppression than blocking erythema, perhaps because only small amounts of the CPD are able to initiate it (15) . Recent research highlights the role of UVA in melanoma development, including DNA damage in melanocytes and inhibition of DNA repair (16). Of particular interest is a study showing that melanin by-products absorb UVA and continue to form CPDs even in the absence of UVA (17). Thus, pigmentation not only protects skin from UV dam- age but may, in some cases, also foster it. Pigmentation occurs after UV-induced stimulation of α-melanin stimulating hormone production which then binds to melano- cortin 1 receptor, promoting tyrosinase activity and melanin formation, and may also stimulate DNA repair (16). On the other hand, another melanocyte-specifi c transcription regulator was shown to turn up pigmentation and turn down DNA repair, and vice versa, in a counterbalancing system (18). DNA REPAIR The broad outlines of nucleotide excision repair (NER) of UV-induced DNA damage were recently reviewed (19,20) A complex of proteins, many also involved in gene tran- scription, identify distortions in DNA produced by photoproducts, and phosphorylation of the xeroderma pigmentosum group C protein within this complex recruits the rest of the NER proteins to the damaged site (21). A length of single-stranded DNA containing the lesion is excised, and the opposite intact strand serves as a template to fi ll in the gap. When DNA replication uses a damaged template, an error-prone polymerase enables replication across the lesion, at the cost of somatic mutations, but with an overall reduc- tion in skin cancer incidence (22). Whereas the entire genome is surveilled for damage by a global repair system, (23) a special system of transcription-coupled repair focuses repair complexes at transcription sites (24,25). This interactive relationship between NER and gene expression was recently