IMPORTANCE OF DNA REPAIR 211 reviewed (26). The physical relationship between transcription factor transcription factor IIH and the NER factor xeroderma pigmentosum group A was visualized, which explains how transcription factors are recruited to NER complexes (27). The complexity of repair- ing DNA bound in nucleosomes and chromatin (7) is solved by the binding of UV-DNA damage-binding protein to UV-damaged nucleosomes and the shifting of nucleosome structure to expose DNA damage (28). An added complexity is the ability of cellular signaling pathways, such as those regulated by cytokines, to modify NER according to the state of the cell, organ, or body (29). Circadian rhythm and the molecular clock affect DNA repair and related responses such as pigmen- tation (30). One consequence of these DNA repair oversight functions is that low, chronic doses increase expression of DNA repair proteins and result in increased repair of CPD but not (6–4) PP (31). Recruitment of DNA repair complexes to damaged sites starts in 1 h and peaks at 6 h (32). (6–4) PP are repaired much faster than the CPD because of their more effi cient recognition and base fl ipping by XPC-Rad4 protein complex (33). Most cellular responses peak at around 6 h while infl ammation, and antigen-specifi c immune suppression signals crest at 24 h. Overall, the half-life of CPDs in the human skin is about 11 h when the system is within its capacity (35), but it becomes saturated just at UV doses that produce a sunburn (36). ENHANCING DNA REPAIR The DNA repair capacity of the skin can be enhanced by delivering DNA repair enzymes. The fi rst patent for a commercial method, using phospholipid liposomes encapsulating enzymes to deliver to skin, was granted in 1991 (37) and enables the delivery of a number of enzymes from a variety of microbial sources, including photolyase from Anacystis nidu- lans, UV endonuclease from Micrococcus luteus, bacteriophage T4 endonuclease V, and 8oGua glycosylase 1 from Arabidopsis thaliana. Recently, others have encapsulated the UV DNA damage endonuclease from yeast and the pyrimidine dimer glycosylase from Paramecium bursaria chlorella virus-1 (38). In each case, the liposome–enzyme composition increased the repair of UV-induced DNA damage. Today, more than 75 skincare products are available that contain DNA repair enzymes, and dozens of clinical studies have reported prevention and enhanced regression of actinic keratosis, nonmelanoma skin cancers, and photoaging (reviewed in ref. 39,40). Indeed, adding DNA repair enzymes to sunscreens provides additive protection (41). The benefi ts appear in a few months, suggesting that enhanced DNA repair reduces short-term cancer- promoting signaling and long-term mutagenic events. Another approach uses nicotinamide (vitamin B3) to overcome UV-induced energy de- pletion and subsequent inhibition of DNA repair (42), and this also reduces the erythe- mal response to a given dose of UV. Studies show that daily ingestion of nicotinamide reduces the number of nonmelanoma skin cancers over a 1-year period in Caucasian skin (42). An intriguing advance was the demonstration that secreted proteins from amnion- derived multipotent progenitor cells applied topically on the human skin immediately after UV irradiation reduced erythema, increased XPA DNA repair protein, and decreased DNA damage (43). Similarly, extracellular vesicles derived from human adipose-derived stem cells, which contain a mixture of miRNAs and proteins, mitigated many effects of UVB irradiation (44).

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