DNA modification and mutation. We are developing genome-scale methods for studying how DNA modifications lead to mutation. Our new Excision-seq and Ribose-seq methods enable high resolution mapping of DNA modification throughout the genome. We aim to use these methods to dissect the mutational process, to understand how hot spots of mutation form in the human genome. We are currently using Excision-seq to study uracilcation of HIV genomes during infection, and mammalian DNA demethylation. We are also extending the method to characterize other types of DNA damage in genomes, including sugar and phosphate modifications.
RNA end modification and fate. We have developed methods to identify RNAs with "dirty" ends that are generated by programmed or unintentional RNA cleavage. We discovered that eukaryotic RNA end modification governs the fate of RNA fragments, poising them for further processing or decay. Moreover, competition between RNA repair and decay regulates an important cellular homeostasis pathway, suggesting that this mode of regulation may be widespread. We are currently developing new methods for identifying RNA with specific end modifications, and are applying these new methods to identify new RNA end modificaiton substrates, and to understand how these modifications impact RNA fate.