Processing of Photoinduced Cross-Links and Monoadducts in Human Cell DNA: Genetic and Molecular Features

Abstract

The interest in cellular processing of DNA interstrand cross-links and monoadducts steins from a number of observations including their induction by a variety of agents present in the human environment. Indeed, several antitumoral drugs (mitomycin C, cis-platinum, nitrogen mustards), environmental pollutants (alkylating agents) and products such as furocoumarins, used in photochemotherapy of certain skin diseases and in cosmetology, have been shown to produce interstrand crosslinks (CL) between either purines or pyrimidines in DNA. In all cases described so far, the production of CL is accompanied by the induction of monoadducts (MA) in various proportions according to the agent used and the treatment conditions. Also, in some cases oxidative type DNA damage is concomitantly induced by cross-linking agents (mitomycin C., for instance) but this type of damage will not be considered further in this report. The presence of such agents in a variety of practical situations provides compelling reasons for predicting and understanding their genotoxic/carcinogenic potentials. Moreover, they constitute attractive model systems to study basic DNA repair mechanisms. In this respect, furocoumarins are of particular interest. These tricyclic aromatic compounds contain two reactive sites, the 3-4 pyrone and the 4′-5′ furan double bonds. They intercalate into DNA and form covalent adducts only with pyrimidine bases after exposure to near ultraviolet light (UVA); when activated by UVA either of the reactive sites of the furocoumarins can react specifically with the 5, 6-double bond of pyrimidine bases forming cyclobutane-type monoadducts on the furan or pyrone-side (MAf or MAp) between a psoralen molecule and a pyrimidine base. Upon absorption of a second photon of 365 nm, a fraction of the 4′, 5′-furan side MA (MAf) can react with a pyrimidine base on the opposite strand by engaging its 3, 4-pyrone double bond to form an interstrand CL (for review, see Cimino, et al., 1985).