O⁶‐alkylguanine‐DNA alkyltransferase: Role in carcinogenesis and chemotherapy

Abstract

The DNA in human cells is continuously undergoing damage as consequences of both endogenous processes and exposure to exogenous agents. The resulting structural changes can be repaired by a number of systems that function to preserve genome integrity. Most pathways are multicomponent, involving incision in the damaged DNA strand and resynthesis using the undamaged strand as a template. In contrast, O(6)-alkylguanine-DNA alkyltransferase is able to act as a single protein that reverses specific types of alkylation damage simply by removing the offending alkyl group, which becomes covalently attached to the protein and inactivates it. The types of damage that ATase repairs are potentially toxic, mutagenic, recombinogenic and clastogenic. They are generated by certain classes of carcinogenic and chemotherapeutic alkylating agents. There is consequently a great deal of interest in this repair system in relation to both carcinogenesis and cancer chemotherapy.

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

“…24,25 These 2 apoptotic stimuli, however, induce different types of DNA damage. Carcinogens such as AOM induce specific DNA adduct and point mutations, 26,27 while radiation induces a much wider spectrum of chromosomal defects such as DNA strand breaks. 28 Thus, p53-dependent apoptosis appears to be an important mechanism for regulation of mutational load that might result from daily exposure to environmental/dietary carcinogens, implying an important regulatory role in oncogenesis for control of exogenous genetic damage.…”

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

“…The contribution of O 6 MeG to cell death depends on the ratio of O 6 MeG to N-alkylations in the DNA, the capacity of the cell to repair O 6 MeG and the rate of repair of N-alkylations (Kaina et al, 1997). The repair of O 6 MeG also provokes protection against the mutagenic, clastogenic and carcinogenic effects of O 6 -alkylating agents, suggesting that O 6 MeG is not only an apoptotic but also a genotoxic (for a review see Margison and Santibanez-Koref, 2002), tumour-initiating (Dumenco et al, 1993;Becker et al, 1996) and tumour-converting (Becker et al, 2003) lesion.…”

Interactions of Human O6-Alkylguanine-DNA Alkyltransferase (AGT) with Short Single-stranded DNAs

“…The ubiquitous repair protein O 6 -alkylguanine-DNA alkyltransferase 4 (AGT, 5 also called O 6 -methylguanine DNA methyltransferase) plays an essential role in maintaining genomic integrity by repairing O 6 -alkylguanine and O 4 -alkylthymine adducts that form in DNA exposed to alkylating agents (1)(2)(3). Both adducts are mutagenic and carcinogenic (1,4,5), whereas O 6 -alkylguanine adducts are also strongly cytotoxic (6).…”