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 The prokaryotic response to UV irradiation, the so-called SOS response, is well documented and is now known to include the induction of a set of >20 genes involved in DNA repair and cell survival (reviewed in ref. 1). In this case, the single-stranded DNA generated after UV irradiation interacts with and activates a protease, the Rec A protein (2). Activated Rec A protein then cleaves and inactivates the repressors of specific genes, leading to their induction (2).In eukaryotic cells, the existence of a UV-induced DNA damage-responsive SOS-like system mediated by one common transcription regulator has been the subject of considerable controversy. Although a variety of genes are known to be induced by DNA damage (3-6), many of these genes are also induced by agents such as phorbol esters (3, 7) and by metabolic or oxidative stress (8-10). Because UV irradiation is reported, like phorbol esters, to activate protein kinase C directly (11,12) and to produce oxidative damage through generation of free radicals from membrane lipids and otherThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. extranuclear cellular constituents, it cannot be determined whether the effects of UV are due directly to DNA damage or instead to other impacts on the cell. Indeed, two of the major UV-induced transcription factors, AP-1 and NF-KB, are now thought to initiate their responses at or near the plasma membrane (13,14).Perhaps the best-characterized example of DNA damagespecific gene induction involves a DNA repair enzyme, photolyase, encoded by the PHR1 gene in Saccharomyces cerevisiae (6). This gene is induced by a variety of DNA-damaging agents including UV light, methyl methanesulfonate (MMS) and 4-nitroquinoline 1-oxide (4-NQO). Up-regulation of PHR1 gene transcription is, at least in part, accomplished by the removal of a damage-responsive repressor which binds to a specific site in the 5' region of the gene (15).Another well-studied UV and DNA damage-inducible gene is the mammalian GADD45 gene. This gene is transcriptionally activated not only by UV irradiation but also by ionizing radiation and chemical agents that specifically cause base damage (10, 16). The induction of GADD45 by ionizing radiation is mediated by the p53 tumor suppressor protein and the ataxia telangiectasia gene product (17), but the UV-and base-damage responses are less well understood. ...

The Regulation of Skin Pigmentation

“…There is increasing evidence that DNA damage/repair itself can induce skin pigmentation. Small DNA fragments, such as thymine dinucleotides, enhance pigmentation of melanocytic cells and can stimulate TYR mRNA levels and responses to MSH (42). p53, which regulates the cell cycle and the repair of DNA damage, as well as the induction of apoptosis (32), can also up-regulate POMC/MSH expression by keratinocytes in response to UV, thereby inducing pigmentation (35).…”

Quantitation and Visualization of Ultraviolet‐Induced DNA Damage Using Specific Antibodies: Application to Pigment Cell Biology

“…There is increasing interest in the roles of UV-induced DNA damage and/or its repair in pigment cell biology, including their role in melanogenesis (tanning) (45)(46)(47), photoprotection and/or photosensitization by melanin (43,48), melanomagenesis (49), etc. Techniques for the quantitation and visualization of UV-induced DNA damage as described in this review may contribute to a better understanding of DNA damage and its biological consequences.…”

An Overactivated ATR/CHK1 Pathway Is Responsible for the Prolonged G2 Accumulation in Irradiated AT Cells

“…In response to ionizing radiation (IR), 1 proliferating cells slow their progress through the cell cycle by activating the DNA damage-induced checkpoints, G 1 , S, and G 2 phase checkpoints, believed to promote DNA repair and to benefit genomic integrity (1)(2)(3)(4). ATM, the protein product of the gene mutated in AT cells, is one such central signal kinase responding to IR (5,6).…”