Accurate DNA replication is essential for genomic stability. One mechanism by which high-fidelity DNA polymerases maintain replication accuracy involves stalling of the polymerase in response to covalent incorporation of mismatched base pairs, thereby favoring subsequent mismatch excision. Some polymerases retain a "short-term memory" of replication errors, responding to mismatches up to four base pairs in from the primer terminus. We recently presented a structural characterization of all 12 possible mismatches captured at the growing primer terminus in the active site of a polymerase [Johnson & Beese, Cell 116, 803]. Our observations suggest four mechanisms that lead to mismatch-induced stalling of the polymerase. Furthermore, we have observed the effects of extending a mismatch up to six base pairs from the primer terminus and we find that long-range distortions in the DNA transmit the presence of the mismatch back to the enzyme active site, suggesting the structural basis for the short-term memory of replication errors.
By contrast with the 12 naturally occurring base-base mismatches, some DNA damage lesions form DNA mispairs that are efficiently extended. Other recent work from our lab [Hsu et al. & Beese, Nature, 431(7005):217-221] demonstrates how one class of lesions inverts the mechanisms of mismatch recognition, leading to recognition of correctly paired nucleotides as mispairs, and vice versa.
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