We study the multiple mechanisms by which cells undergo mutation. In effect, this is a detailed investigation into the broad range of genetic and enzymatic mechanisms by which cells try to avoid making mutations. We use as model system the bacterium Escherichia coli, employing genetic and biochemical approaches. We study both mutator (elevated mutation rates) and antimutator (reduced mutation rates) organisms. The study of mutators provides insights into the operative mutation prevention systems, while the study of antimutators provides insight into the actual sources of mutations [such as errors of DNA replication, DNA repair errors, unrepaired DNA damages, or altered DNA precursor pools (dNTPs)]. Specifically, our lab investigates: (i) the fidelity of the multi-subunit DNA replication complex responsible for the simultaneous replication of leading and lagging strands, including the role played by individual subunits of this complex, (ii) the role of the accessory DNA polymerases in chromosomal replication, (iii) the role of the deoxynucleoside triphosphate DNA precursors (dNTPs) in determining in vivo replication error rates, (iv) the mechanisms used to maintain "clean" cellular dNTP pools by removing mutagenic and toxic derivatives (pool sanitation), and (v) novel molybdenum-cofactor-dependent activities that we have discovered in E. coli that detoxify N-hydroxylated base analogs and related chemical compounds. Major areas of research: Sources of mutations Mechanisms of DNA replication fidelity Base selection, proofreading, mismatch repair Mutator and antimutator mechanisms Role of dNTP precursors in replication fidelity