title: DNA damage enhances melanogenesis.
abstract: Although the ability of UV irradiation to induce pigmentation in vivo and in vitro is well documented, the intracellular signals that trigger this response are poorly understood. We have recently shown that increasing DNA repair after irradiation enhances UV-induced melanization. Moreover, addition of small DNA fragments, particularly thymine dinucleotides (pTpT), selected to mimic sequences excised during the repair of UV-induced DNA photoproducts, to unirradiated pigment cells in vitro or to guinea pig skin in vivo induces a pigment response indistinguishable from UV-induced tanning. Here we present further evidence that DNA damage and/or the repair of this damage increases melanization. (i) Treatment with the restriction enzyme Pvu II or the DNA-damaging chemical agents methyl methanesulfonate (MMS) or 4-nitroquinoline 1-oxide (4-NQO) produces a 4- to 10-fold increase in melanin content in Cloudman S91 murine melanoma cells and an up to 70% increase in normal human melanocytes, (ii) UV irradiation, MMS, and pTpT all upregulate the mRNA level for tyrosinase, the rate-limiting enzyme in melanin biosynthesis. (iii) Treatment with pTpT or MMS increases the response of S91 cells to melanocyte-stimulating hormone (MSH) and increases the binding of MSH to its cell surface receptor, as has been reported for UV irradiation. Together, these data suggest that UV-induced DNA damage and/or the repair of this damage is an important signal in the pigmentation response to UV irradiation. Because Pvu II acts exclusively on DNA and because MMS and 4-NQO, at the concentrations used, primarily interact with DNA, such a stimulus alone appears sufficient to induce melanogenesis. Of possible practical importance, the dinucleotide pTpT mimics most, if not all, of the effects of UV irradiation on pigmentation, tyrosinase mRNA regulation, and response to MSH without the requirement for antecedent DNA damage.
authors.affiliation: Department of Dermatology, Boston University School of Medicine, MA 02118-2394, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Eller
authors.forename: K
authors.initials: K
authors.lastname: Ostrom
authors.forename: B A
authors.initials: BA
authors.lastname: Gilchrest
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002462:Cell Membrane / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D015252:Deoxyribonucleases, Type II Site-Specific / Q000494:pharmacology; D015226:Dinucleoside Phosphates / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D008543:Melanins / Q000096:biosynthesis*; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism / Q000494:pharmacology; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D008546:Melanoma, Experimental / Q000378:metabolism; D008741:Methyl Methanesulfonate / Q000633:toxicity; D051379:Mice; D014442:Monophenol Monooxygenase / Q000096:biosynthesis*; D011979:Receptors, Pituitary Hormone / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D002273:Carcinogens; D015226:Dinucleoside Phosphates; D008543:Melanins; D011979:Receptors, Pituitary Hormone; C017758:thymidylyl-(3'-5')-thymidine; D015112:4-Nitroquinoline-1-oxide; C029446:MSH receptor; D009074:Melanocyte-Stimulating Hormones; D008741:Methyl Methanesulfonate; D014442:Monophenol Monooxygenase; C025630:CAGCTG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific