Enhancement of DNA repair in human skin cells by thymidine dinucleotides: Evidence for a p53-mediated mammalian SOS response

Abstract

Thymidine dinucleotide (pTpT) stimulates melanogenesis in mammalian pigment cells and intact skin, mimicking the effects of UV irradiation and UV-mimetic DNA damage. Here it is shown that, in addition to tanning, pTpT induces a second photoprotective response, enhanced repair of UV-induced DNA damage. This enhanced repair results in a 2-fold increase in expression of a UV-damaged chloramphenicol acetyltransferase expression vector transfected into pTpTtreated skin fibroblasts and keratinocytes, compared with diluent-treated cells. Direct measurement of thymine dimers and (6-4) photoproducts by immunoassay demonstrates faster repair of both of these UV-induced photoproducts in pTpT-treated fibroblasts. This enhanced repair capacity also improves cell survival and colony-forming ability after irradiation. These effects of pTpT are accomplished, at least in part, by the up-regulation of a set of genes involved in DNA repair (ERCC3 and GADD45) and cell cycle inhibition (SDI1). At least two of these genes (GADD45 and SDI1) are known to be transcriptionally regulated by the p53 tumor suppressor protein. Here we show that pTpT activates p53, leading to nuclear accumulation of this protein, and also increases the specific binding of this transcription factor to its DNA consensus sequence.

Cyclic AMP a Key Messenger in the Regulation of Skin Pigmentation

“…Additionally, a new concept has emerged from the work of Dr. B. Gilchrest's group (30). These works suggest that DNA damage and DNA repair play relevant roles in the UV-induced melanogenic response of melanocytes.…”

Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53

“…In this respect, p53 behaves like other proteins that are directly involved in DNA repair. But not only does a defect in p53 function result in a defective DNA repair, the induction of p53 after a (Eller et al, 1997).…”

Base excision DNA repair defect in Gadd45a-deficient cells

“…Additionally, a deoxyribonucleotide phosphate lyase is a rate-limiting component. The concept that DNA repair levels in mammalian cells are regulated has major implications for cancer prevention (Eller et al, 1997) and therapy (Fan and Bertino, 1999).…”