Fig. 5. Model for repeat instability at the FX locus.
Repair synthesis or transcription could provide an opportunity for secondary structure formation by both strands of the FX repeat. The resultant “double hairpin” may resemble a Holliday junction (HJ) that can be processed by MutLγ to generate a staggered DSB within the repeat. Since the staggered ends each contain CGG repeats they are complementary and can thus anneal without need for end-resectioning. This product could then be processed by NHEJ to generate contractions or to restore the original repeat tract. Out of register annealing of the staggered ends could be processed by an alternative pathway such as gap filling to generate expansions.