The lyase activity of the DNA repair protein beta-polymerase protects fromDNA-damage-induced cytotoxicity

Small DNA lesions such as oxidized or alkylated bases are repaired by the b ase excision repair (BER) pathway(1). BER includes removal of the damaged b ase by a lesion-specific DNA glycosylase, strand scission by apurinic/apyri midinic endonuclease, DNA resynthesis and ligation(2). BER may be further s ubdivided into DNA beta-polymerase (beta-pol)-dependent single-nucleotide r epair and beta-pol-dependent or -independent long patch repair subpathways( 3-6). Two important enzymatic steps in mammalian single-nucleotide BER are contributed by beta-pol: DNA resynthesis of the repair patch and lyase remo val of 5'-deoxyribose phosphate (dRP)(2). Fibroblasts from beta-pol null mi ce are hypersensitive to monofunctional DNA-methylating agents, resulting i n increases in chromosomal damage, apoptosis and necrotic cell death(3,7). Here we show that only the dRP lyase activity of beta-pol is required to re verse methylating agent hypersensitivity in beta-pol null cells. These resu lts indicate that removal of the dRP group is a pivotal step in BER in vivo . Persistence of the dRP moiety in DNA results in the hypersensitivity phen otype of beta-pol null cells and may signal downstream events such as apopt osis and necrotic cell death.