Fig. 4. Model for the bypass of (6–4)TT and G-AAF lesions in S.cerevisiae. (A) (6–4)TT. Data presented here suggest that, in vivo, Pol η inserts G ‘incorrectly’, while another polymerase inserts A ‘correctly’ opposite the 3′-T of the (6–4)TT lesion. In a wild-type background, both events occur at similar frequencies: 60% of misinsertion versus 40% of error-free insertion. Following this insertion step, both replication intermediates are likely to be extended by Pol ζ, yielding mutagenic and error-free bypass products, respectively (see text for discussion). (B) G-AAF. Within the 3TG sequence context, G-AAF adducts are mostly bypassed in an error-free manner. However, the adduct may also trigger a slippage event in the primer strand during replication of three Ts located 5′ to the adduct, thus yielding a +T frameshift mutation (semi-targeted frameshift event). As inactivation of Pol η suppresses 75% of all bypass events, we suggest that Pol η is involved mainly at the insertion step, and Pol ζ at the extension steps, yielding both error-free and frameshift bypass events. In the absence of Pol η, yet another DNA polymerase appears to perform limited insertion, as shown by the thin arrow (see text for further details).