INHIBITION BY NITRIC-OXIDE OF THE REPAIR PROTEIN, O(6)-METHYLGUANINE-DNA-METHYLTRANSFERASE

Nitric oxide (NO) has been shown to be involved in a number of physiol ogical processes. In the presence of oxygen, this reactive diatomic mo lecule is capable of generating reactive nitrogen oxide species (NOx) which possess both nitrosating and oxidizing ability for various subst rates, including certain biological macromolecules. This report shows the inhibition of the DNA repair protein, O-6-methylguanine-DNA-methyl transferase, by Et(2)N[N(O)NO]Na (DEA/NO), a compound which decomposes with concurrent release of NO. The inhibition of the purified transfe rase activity by NO was dose- and time-dependent and the extent of inh ibition by DEA/NO corresponded to the total quantity of NO released. T his inhibitory effect by NO was also demonstrated to be reversible ove r time. The reaction of the NO released from DEA/NO with cysteine unde r aerobic conditions resulted in the formation of an S-nitrosothiol ad duct, suggesting that a similar adduct could be responsible for the in activation.