What is the effect of the switching between BER and recombination for alkylation induced cellular damage? In yeast, it has been shown that BER (Mag-1 initiated) and recombinational repair show a complex genetic interaction that determines alkylation resistance (51,52). It was therefore hypothesized that BER intermediates might be responsible for Mag1-induced recombination. In mammalian cells, it was shown that MMS induces a dramatic increase in SCE in cells lacking Pol b (4). These cells present relatively more SCE than 3-methyladenine DNA glycosylase (Aag) and Aag/Pol b cells, suggesting that unrepaired 50-dRP lesions can stimulate HR (8). We propose that in Pol b cells, the accumulation of SSB triggers the HR pathway following DSB formation, thus limiting the cytotoxic effects of alkylation damage. Defects in the recombination pathway are expected to lead to more dramatic effects on alkylation damage- sensitive phenotype than BER defects. In conclusion, we propose that, in the absence of Pol b, SSB (likely due to persistent 50dRP residues) accumulate in G1 phase cells. When these lesions encounter the replication machinery the replication forks collide. A fraction of these events leads to replication-mediated DSB formation (g H2AX foci formation). The replication-mediated DSB would trigger recombination and activate a checkpoint response. HR will partially compensate for the BER defect to avoid excessive alkylation-induced cytotoxicity. ACKNOWLEDGEMENTS We are grateful to E. Prosperi for helpful comments and suggestions during all stages of the project. This work was partially supported by the Associazione Italiana Ricerca sul Cancro (A.I.R.C.) and by Compagnia di S. Paolo, Turin, Italy (Project coordinator: Dr G. Frosina). Funding to pay the Open Access publication charges for this article was provided by Associazione Italiana Ricerca sul Cancro (A.I.R.C.). REFERENCES 1. 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