We have examined the role of the catalytic lysine (Lys 249) in breaking the glycosidic bond of 8-oxoguanine in the enzyme human 8-oxoguanine DNA glycosylase. Until quite recently it has been assumed that this lysine acts as a nucleophile in an S(N)2 type of reaction after being activated through a donation of a proton to a strictly conserved aspartate, also located in the active site. However, evidence from crystallographic, as well as biochemical studies, questions this assumption mainly because the lysine is not ideally positioned for such an attack. In addition, the catalytic activity is preserved even after that aspartate is mutated to a residue not accepting protons, but still keeping the interactions in the active site. In this study, we have investigated several different reaction mechanisms to discover plausible ways where the lysine could assist in breaking the glycosidic bond. We use hybrid density functional theory to characterize both associative and dissociative pathways. We find that the smallest energetical barrier involves an S(N)1 type of mechanism where the lysine electrostatically stabilizes the dissociating base and then donates a proton with a very small barrier and then finally attacks the sugar ring to create the covalently bound protein-DNA intermediate complex. The S(N)2 mechanism also has a lower barrier than the "spontaneous" bond breaking but considerably above that of the S(N)1 reaction. However, in current conditions, the reactants placed in a conformation posed for an S(N)2 reaction is substantially more stable than if posed for the S(N)1 reaction, indicating that the active site has to bind stronger to the latter in order to achieve a full catalytic effect. An analysis of the polarization of the transition states shows that the polarization is largest for the S(N)1 reaction, indicating that this path will gain most by being placed in a prepolarized active site. These findings give further support to the hypothesis that a dissociative mechanism may be the preferred mode of action for this type of enzymes.