Structure-Function Studies Of DNA Replication Fidelity

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This year, sometimes with the group only and other times in collaboration with scientists in other groups within NIH and elsewhere, we had several accomplishments. (1) We identified and genetically characterized a mutator derivative of yeast DNA polymerase zeta, which has a critical role in determining the rate of both spontaneous and DNA damage-induced mutagenesis in eukaryotes. (2) We published several studies that reveal the roles of DNA polymerases delta and epsilon in replicating the leading and lagging strands on the nuclear genome. (3) We demonstrated that trace amounts of 8-oxo-dGTP in mitochondrial dNTPs reduce DNA polymerase gamma replication fidelity, thereby possibly contributing to mitochondrial genome instability associated with mitochondrial diseases. (4) We provided evidence that DNA strand misalignment during catalytic cycling by DNA polymerase lambda occur during dNTP-induced repositioning of the template strand. (5) We demonstrated that DNA polymerase lambda can function in joining broken DNA ends even when these ends contain lesions. (6) We demonstrated low fidelity DNA synthesis by human DNA polymerase theta, consistent with its possible roles in translesion DNA synthesis and somatic hypermutation of immunoglobulin genes, (8) We investigated the catalytic mechanism for correct nucleotide incorporation by human DNA polymerase lambda with Mg2+ and Mn2+ using ab initio QM/MM studies. (9) We published comprehensive reviews on (a) structure-function relationships among the four mammalian X family DNA polymerases, (b) TLS polymerases and (c) the roles of the major eukaryotic replicative DNA polymerases.