Principal Investigator Leona Samson
We are studying the biology of E. coli AlkB and its human relatives, hABH1, hABH2 and hABH3. AlkB has long been known to play a role in protecting cells from alkylation damage, and only recently has it been shown to repair damaged cytosine and adenine in DNA through a novel mechanism, oxidative demethylation. Surprisingly, AlkB and hABH3 can even repair RNA.
We are also studying DNA repair pathways dealing with alkylated base lesions present in cellular DNA. (i) Base excision repair (BER), initiated when the damaged base is enzymatically removed by a 3-methyladenine (3MeA) DNA glycosylase. (ii) Direct reversal of base damage wherein the unwanted alkyl group on O6-methylguanine (O6-MeG) is transferred to a DNA repair methyltransferase (MTase), thus inactivating the MTase and restoring the normal DNA base.
We are examining the global transcriptional response of mammalian cells and tissues to carcinogenic alkylating agents, and in addition to examine the details of this global picture that represent the response elicited by the presence of specific alkylated bases in the genome (e.g., 3MeA and O6MeG). For this, we exploit two knock-out mouse model systems that we recently generated. One is deficient in 3MeA DNA glycosylase repair activity (Aag null mice), and the other is deficient in the O6-MeG DNA repair MTase activity (Mgmt null mice).