The competing mini-dumbbell mechanism: new insights into CCTG repeat expansion

A dynamic model of DNA behavior may explain the mechanism by which repetitive sequences accumulate in a rare human disease. Myotonic dystrophy 2 arises from the presence of numerous tandem copies of the CCTG nucleotide sequence in a particular gene. Pei Guo and Sik Lok Lam of The Chinese University of Hong Kong set out to ascertain why cellular DNA repair mechanisms fail to eliminate the extra CCTG repeats in myotonic dystrophy 2 patients. Short stretches of the CCTG sequence can form ‘mini-dumbbell’ structures, which contribute to the addition of extra CCTG repeats during DNA replication. Lam and Guo demonstrated that these mini-dumbbells produce distinctive loops in the DNA strand. They further showed that these loops can dynamically slide back and forth along the DNA strand, enabling them to elude correction and fueling further repeat accumulation.