3059 Dibenzo[a,l]pyrene (DB[a,l]P), a very potent carcinogenic polycyclic aromatic hydrocarbon (PAH), adaptively induces base excision repair (BER) genes, including DNA polymerase β (Polβ) in mouse skin (Chakravarti et al., Proc Am Assoc Cancer Res, 2004). This response is correlated with mutagenesis from the rapidly formed apurinic sites generated by DB[a,l]P-induced depurinating DNA adducts. Therefore, Polβ may be a candidate for inducing mutations by erroneous BER. Polβ also modulates abasic site-induced cytotoxicity by removing dRP residues generated during BER. We investigated the cytotoxic and mutagenic roles of Polβ in response to apurinic sites induced by DB[a,l]P in mouse fibroblasts with an isogenic defect in Polβ (Mβ16 tsA, Polβ+, and Mβ19 tsA, Polβ-). DB[a,l]P, which rapidly generates apurinic sites, induced significantly more cytotoxicity in the Polβ+ cells than Polβ- cells. Low doses of DB[a,l]P did not show an adaptive resistance to cytotoxicity to a second (challenge) dose of DB[a,l]P. Although the adaptive response was not observed, we obtained evidence for the role of DB[a,l]P-induced abasic sites in mediating cytotoxicity in Polβ+ cells. Specifically, the cytotoxic response of DB[a,l]P could be potentiated by methoxyamine, which reacts with abasic sites to form conjugates that interfere with BER. DB[a,l]P treatment resulted in the induction of abundant amounts of A.T to G.C mutations in Polβ+ cells, but not in Polβ- cells. The induction of the A.T to G.C mutations in Polβ+ cells could be blocked by methoxyamine. These results strongly suggest that apurinic sites induced by DB[a,l]P are involved in inducing cytotoxicity and mutations in a Polβ-dependent manner (Supported by NIH grants P20-RR017675 and PO1 CA 49210).