FIG 6.

Role of the mismatch repair system in CAG/CTG trinucleotide repeat expansion and fragility. (A) Hairpin formed on the newly synthesized lagging strand. The damaged fork is recognized by the MMR but cannot be fixed, thus leading to a small expansion during the next S phase. Successive cycles of small expansions may occur, ultimately leading to a large expansion. Alternatively, another mechanism may directly lead to large expansions, such as those observed in some human disorders. Unrepaired heteroduplex DNA is observed in the progeny as two cell populations with different repeat tract lengths (see the text for details). (B) Hairpin formed on the lagging-strand template. The damaged fork is recognized by the mismatch repair system (MMR) and may lead to chromosomal fragility at the next S phase if checkpoints are bypassed or if the damage cannot be fixed. Template switching is a possible pathway to repair and restart the fork but may lead to trinucleotide repeat expansions and contractions by homologous recombination under the control of the Rad51 recombinase and the Srs2 helicase in yeast (see the text for details). Note that the hairpin was drawn on the lagging strand (or on its template), but the model can perfectly be reversed if its formation happens on the leading strand (or on its template).