The Biology of the (6–4) Photoproduct

Abstract

The (6-4) photoproduct is an important determinant of the lethal and mutagenic effects of UV irradiation of biological systems. The removal of this lesion appears to correlate closely with the early DNA repair responses of mammalian cells, including DNA incision events, repair synthesis and removal of replication blocks. The processing of (6-4) photoproducts and cyclobutane dimers appears to be enzymatically coupled in bacteria and most mammalian cell lines examined (i.e. a mutation affecting the repair of one lesion also often affects the other), although exceptions exist in which repair capacity may be evident for one photoproduct and not the other (e.g. UV61 and the XP revertant cell line). These differences in the processing of the two photoproducts in some cell lines of human and rodent origin suggest that in mammalian cells, different pathways for the repair of (6-4) photoproducts and cyclobutane dimers may be used. This observation is further supported by pleiotropic repair phenotypes such as those observed in CHO complementation class 2 mutants (e.g., UV5, UVL-1, UVL-13, and V-H1). Indirect data, from HCR of UV irradiated reported genes and the cytotoxic responses of UV61, suggest that the (6-4) photoproduct is cytotoxic in mammalian cells and may account for 20 to 30% of the cell killing after UV irradiation of rodent cells. Cytotoxicity of the (6-4) photoproduct may be important in the etiology of sunlight-induced carcinogenesis, affecting mutagenesis as well as tumorigenesis. The intricate photochemistry of the (6-4) photoproduct, its formation and photoisomerization, is in itself extremely interesting and may also be relevant to sunlight carcinogenesis. The data reviewed in this article support the notion that the (6-4) photoproduct and its Dewar photoisomer are important cytotoxic determinants of UV light. The idea that the (6-4) photoproduct is an important component in the spectrum of UV-induced cytotoxic damage may help clarify our understanding of why rodent cells survive the effects of UV irradiation as well as human cells, without apparent cyclobutane dimer repair in the bulk of their DNA. The preferential repair of cyclobutane dimers in essential genes has been proposed to account for this observation (Bohr et al., 1985, 1986; Mellon et al., 1986). The data reviewed here suggest that understanding the repair of a prominent type of noncyclobutane dimer damage, the (6-4) photoproduct, may also be important in resolving this paradox.

Nicotinamide, a missing link in the early stress response in eukaryotic cells: A hypothesis with special reference to oxidative stress in plants

“…This also indicates that these treatments may induce DNA-strand breaks in plant tissues. In human skin, DNA-strand breaks constitute a considerable portion of the lesions caused by UV-B and UV-A exposure [38]. However, yeast elicitor did not cause increased levels of the nicotinamide metabolites nicotinic acid-N-glucoside and/or trigonelline in cell suspensions cultures of N. tabacum [39].…”

DNA photolyases of Chrysodeixis chalcites nucleopolyhedrovirus are targeted to the nucleus and interact with chromosomes and mitotic spindle structures

“…Based on sequence comparisons, these genes encode DNA photolyases specific for cyclobutane pyrimidine dimers (CPDs), and it has been suggested that these genes are involved in viral DNA repair (van Oers et al, 2005). CPDs as well as pyrimidine 6-4 pyrimidone photoproducts [(6-4)PP] are formed upon exposure of genomic DNA to UV light (UVB, 280-320 nm), but CPDs constitute the majority of UV-induced DNA lesions (Mitchell & Nairn, 1989;Rycyna & Alderfer, 1985;Setlow & Carrier, 1966). Dimeric pyrimidine photoproducts are cytotoxic, as they block transcription, may induce mutations and trigger apoptosis (Ljungman & Zhang, 1996;Nishigaki et al, 1998;Chiganças et al, 2002).…”

The Dewar photoproduct of thymidylyl(3′→5′)- thymidine (Dewar product) exhibits mutagenic behavior in accordance with the “A rule”

“…Although both the pyrimidine (6-4)pyrimidone photoproduct [ adduct], which is one of the major classes of UV-induced DNA photoproducts (9,10), and its Dewar valence isomer (Dewar product) (Fig. 1A) cause mutations during TR, their mutagenic properties differ.…”