Group Leader:
Geoff Margison
I first joined the Department of Chemical Carcinogenesis at the (then) Paterson Laboratories, in 1966 as a research technician. In 1967, I went to Manchester University, obtained a BSc degree and then returned to the Paterson to undertake a Ph.D. studying the biochemical effects of chemical methylation of DNA. I obtained my Ph.D. in 1973. My first postdoctoral fellowship was at the Max-Planck Institute for Brain Research in Cologne, Germany, between 1973-1975, before accepting a visiting fellowship at the International Agency for Research on Cancer in Lyon, France. I rejoined the Cancer Research Campaign Carcinogenesis Department (which became Cancer Research UK Carcinogenesis Group), at the Paterson in 1976. I was awarded a tenure in 1978, a Special Appointment in 1992 and since 1997 have been Group Leader.
Postdoctoral Fellow
Vitaly Latypov
Scientific Officers
Mandy Watson
Gail McGown
Mary Thorncroft
Graduate Student
Andrew Marriott
Carcinogenesis Group - O6-alkylguanine-DNA alkyltransferase
Repair pathways, which may have evolved to deal with low levels of DNA damage, reduce the efficacy of 'O6-alkylating' agents. Certain tumour types, such a breast tumours, can express high levels of repair proteins and are generally ressitant to O6-alkylating agents. On the other hand, some normal tissues, such as the bone marrow cells, express very low levels and it is this that prevents higher doses of O6-alkylating agents being used clinically. There is therefore increasing interest in developing strategies to modulate the expression of such pathways. These approaches aim mainly to suppress repair in order to enhance tumour response, but strategies are also being developed to increase normal tissue repair capacity, in particular by gene transfer and expression in haemopoietic cells. Most attention has been directed to the pathway involved in repairing damage at the O6-position of guanine in DNA i.e. O6-alkylguanine-DNA alkyltransferase (also known as AGT; the human version being called MGMT). The mechanism of action of MGMT involves the removal of alkyl groups from the O6-position of guanine, by stoichiometric transfer to a cysteine residue in the active site of the protein, a process that results in its irreversible inactivation. Small molecule “pseudosubstrates” of MGMT, such as PaTrin-2 are in clinical trial in combination with O6-alkylating drugs.
Click Here to open a powerpoint presentation describing how MGMT works.