Abstract
The effect of S-substitution on the O6 guanine site of a 13-mer DNA duplex containing a G:T mismatch is studied using molecular dynamics. The structure, dynamic evolution and hydration of the S-substituted duplex are compared with those of a normal duplex, a duplex with S-substitution on guanine, but no mismatch and a duplex with just a G:T mismatch. The S-substituted mismatch leads to cell death rather than repair. One suggestion is that the G:T mismatch recognition protein recognises the S-substituted mismatch (GS:T) as G:T. This leads to a cycle of futile repair ending in DNA breakage and cell death. We find that some structural features of the helix are similar for the duplex with the G:T mismatch and that with the S-substituted mismatch, but differ from the normal duplex, notably the helical twist. These differences arise from the change in the hydrogen-bonding pattern of the base pair. However a marked feature of the S-substituted G:T mismatch duplex is a very large opening. This showed considerable variability. It is suggested that this enlarged opening would lend support to an alternative model of cell death in which the mismatch protein attaches to thioguanine and activates downstream damage-response pathways. Attack on the sulphur by reactive oxygen species, also leading to cell death, would also be aided by the large, variable opening.
Highlights
6-thioguanine, (Fig 1a), is an important drug against childhood leukaemia and its effects are thought to be due to its incorporation into DNA [1]
First we consider the effect of the G:T mismatch on the duplex structure and the effect of GS
The structure and dynamics of the G:T mismatched oligomer is important as it is differences in these properties from those of the normal oligomer that are likely to be detected by the repair mechanism
Summary
6-thioguanine, (Fig 1a), is an important drug against childhood leukaemia and its effects are thought to be due to its incorporation into DNA [1]. The incorporation of 6-thioguanine (which we shall designate GS) does not lead to disruption of the overall structure of DNA, there is evidence that it renders one of the DNA repair mechanisms less efficient. The 4-amino group of 5-methylcytosine of the G: MeC pair is deaminated to form thymine (see Fig 1b) resulting in a G:T pair. Such a mismatch would lead to a G:C to A:T mutation and alteration of the code with possibly deleterious biological effects. Yuan et al [2] have shown that such a mutation occurs with GS:C
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