Molecular mechanisms of mammalian DNA repair

Mutations are the fundamental cause of all forms of cancer and a number of different, but integrated processes operate to prevent such genetic changes from occurring. DNA repair is of fundamental importance in limiting the occurrence of mutations. We will carry out comprehensive studies on the mechanisms of DNA repair and the regulation of such processes by macromolecular interactions, post translational modifications, subcellular transport, damage induction and cell cycle expression. The emphasis researc h team will be upon base excision repair, single strand break repair and alkylation repair. Collaborative studies will reveal novel structural aspects of DNA repair. The use of affinity-isolated repairosomes, together with mass spectrometry and confocal m icroscopy, will facilitate mechanistic aspects and knockout mice will contribute to a better understanding of functions.We have recently demonstrated, in collaboration with prof. E.C. Seeberg's group, that human AlkB homologues hABH2 and hABH3 repair 1-me thyladenine and 3-methylcytosine in DNA by oxidative demethylation, like AlkB itself. Surprisingly, AlkB and hABH3, but not hABH2, also repair the corresponding methyations in RNA, both in vitro, and when expressed in E. coli, thus establishing RNA repair as a new defence mechanism of potential significance. The new doctoral student whom we apply for support for will be working with the biochemistry and function of human alkB homologues. She will also contribute to the work with mice deficient in hABH1, h ABH2 or hABH3, as well as double and triple knock-outs. These are already well underway and the project will be carried out in collaboration with Drs. Seeberg and Klungland.