New Players in Recognition of Intact and Cleaved AP Sites: Implication in DNA Repair in Mammalian Cells

Abstract

The apurinic/apyrimidinic (AP) sites (called also abasic sites) are common lesion in genomic DNA, arising at a frequency of 10,000 to 50,000 lesions per mammalian cell per day (Lindahl, 1993). Unrepaired AP sites present mutagenic and cytotoxic consequences to the cell (Wilson; & Thompson, 1997). Most of the abasic sites are believed to result directly from spontaneous depurination, or indirectly from deamination of cytosine to uracil, which is then eliminated by uracil glycosylases. AP sites also result from hydrolysis of oxidized or alkylated bases by lesion-specific glycosylases during the early stage of base excision repair (BER) (McCullough et al., 1999). AP sites in isolated DNA are rather stable, but can be converted to single-strand breaks by alkali treatment, heating or nucleophilic attack at the aldehydic C1’ group (Burrows & Muller, 1998). Intact abasic sites are noncoding lesions and in vivo can be stable enough to be mutagenic during DNA replication (Loeb & Preston, 1986). To protect genome integrity, eukaryotic organisms have robust enzyme activities, mainly APE1 in mammalian cells (Wilson & Barsky, 2001), that recognize abasic sites and cut the DNA backbone initiating the repair process. The continuous generation and repair of AP sites results in a steady-state levels of AP sites in mammalian cells in the range of approximately 1 site per 106 nucleotides (Atamna et al., 2000, Mohsin Ali et al., 2004). The number of AP sites can increase dramatically under stressful conditions such as X-ray or UV light irradiation or oxidative and alkylating agent exposure (Atamna et al., 2000). Considering the ubiquity of these lesions, it is reasonable to assume that wide range of cellular proteins can interact with abasic sites depending on the physiological state and stages of cell cycle. The chapter is devoted to search of previously unrecognized proteins capable to interact with intact or cleaved AP sites. We mainly focused on proteins that form Schiff base upon this interaction. In most cases, these proteins are able to process AP sites although less efficiently than previously known counterparts. The biological role of these interactions in providing of backup pathways of DNA repair processes is also discussed.