Models of Repair Underlying Trinucleotide DNA Expansion

This chapter focuses on repair-dependent models for the expansion at a DNA break. The first and most straightforward mechanism proposed for DNA opening and expansion was polymerase slippage during mitosis. In this model, the polymerase dissociates from the repeat segment on the template strand during DNA synthesis and "slips" back to pair at a previously replicated triplet unit. The replicated repeat DNA forms an extrahelical loop that can be incorporated into the DNA. Although unpairing reactions in duplex DNA are energetically unfavorable, slippage during DNA synthesis is possible because the unpairing reaction occurs largely when polymerase falls off the DNA. Because hydrogen-bonded structures appear to be important intermediates in expansion, rapid and stable intrastrand hydrogen bonding is likely to allow extrahelical structures to prevail over duplex reannealing. However, a mitotic replication model predicts that slippage should occur in both the daughter and the template strands, and a relatively equal number of expansion and contraction events would be expected.