This year, our group published 12 scientific articles related to DNA replication and its fidelity. We showed that ribonucleotides incorporated during eukaryotic nuclear DNA replication are subject to removal by a mutant derivative of RNase H2 that is defective in repairing ribonucleotides incorporated during yeast DNA replication but retains the ability to resolve R-loops formed during transcription. We showed that formation of double strand DNA breaks due to ribonucleotide incorporation during DNA replication result in genome instability. These breaks are due to topoisomerase 1 incision of ribonucleotides incorporated by DNA polymerase epsilon, the primary leading strand replicase. We collaborated with others to describe three aspects of non-homologous end joining of double strand breaks in DNA: 1) the X ray crystal structure of DNA polymerase mu bound to a ribonucleotide, 2) the X ray crystal structure of Pol mu showing a third divalent metal ion that is involved in DNA synthesis, and 3) an X ray crystal structure showing for the first time how DNA ligase 1 binds to a primer-template, revealing how it conducts ligation to complete repair. We studied the properties of a yeast strain lacking the catalytic activity of Pol epsilon, and demonstrated that this activity is important for accurate replication of the majority of leading DNA strand synthesis, while also demonstrating that Pol delta is important for a small but critical step in replication at origins. We collaborated with two other principal investigators to show that RNH-H2 is a tumor suppressor genes for skin and colon cancer in mice. Finally, we published four review articles in the DNA replication field.
Showing the most recent 10 out of 72 publications
