Hypothetical models illustrating CTG repeat instability governed by the positions of oxidative DNA base lesions through pol β and FEN1.

<p>Oxidative stress can result in an oxidized DNA base lesion, 8-oxoG that is located either at the 5′-end, in the middle, or at the 3′-end of CTG repeats. Removal of the damaged site by OGG1 leaves an abasic site that is subsequently 5′-incised by APE1 generating ssDNA breakage, results in the formation of multiple hairpins on repeat tracts. A base lesion that occurs at the 5′-end of the repeats allows the formation of a multi-nucleotide gap and subsequently a 5′-hairpin along with a template hairpin. Pol β passes through the template hairpin and synthesizes more repeats than those removed by FEN1, thereby causing repeat expansions (sub-pathway <b>1</b>). A base lesion located in the middle of CTG repeats results in the formation of an upstream hairpin and a downstream hairpin in the damaged strand along with two template hairpins. The upstream hairpin leads to inefficient pol β DNA synthesis that inserts one or two repeats, but allows FEN1 to remove more repeats than those synthesized by pol β, leading to small repeat deletions (sub-pathway <b>2</b>). A base damage located at the 3′-end of repeats immediately adjacent to the random sequence region, allows the formation of a large upstream hairpin and a template hairpin. Pol β inserts one to three nucleotides to fill a single-nucleotide gap. In this scenario, repeats in the upstream strand cannot be processed by repair activities, thereby leading to maintenance of repeat length (sub-pathway <b>3</b>). When two base lesions simultaneously occur at the 5′-end and in the middle of CTG repeat tracts, two hairpins in the damaged strand and two template hairpins would form. This leads to efficient pol β DNA synthesis that can strand-displace the hairpin in between two damage sites, resulting in loss of large numbers of repeats. Efficient FEN1 cleavage of the 5′-downstream CTG repeats leads to additional shortening of repeats. The cooperation between pol β strand-displacement synthesis and FEN1 cleavage leads to large repeat deletions (sub-pathway <b>4</b>).