Romancing Mutators: Understanding Mechanisms of Directed Mutation in Humans

The main long-term goal of my laboratory is to understand the physiological roles and pathological consequences of programmed mutation in humans. Mutations drive evolution and are mostly responsible for the tremendous variation observed between different organisms and even within an individual species. Most mutations are thought to occur spontaneously, without a direct or immediate need for their utility. However, this is not always the case as at least two important physiological processes - antibody gene diversification and retroelement restriction - are triggered by the deamination of DNA cytosines to uracils. The human proteins responsible are called AID and APOBEC3F/G, respectively. These proteins are potent DNA mutators that must be directed to their specific physiological targets, to immunoglobulin genes or to retroviruses (e.g., HIV-1) and retrotransposons. We are using a number of model systems to understand how AID and APOBEC3 proteins are regulated at the post-translational level. We anticipate that both unique and common themes will emerge. Moreover, we expect that by understanding how these proteins are regulated normally, we will gain insight into the possible consequences when they are not (e.g., cancer).

Please see the Harris laboratory website for further information.