Effects of interrupting residues on DNA dumbbell structures formed by CCTG tetranucleotide repeats associated with myotonic dystrophy type 2

Myotonic dystrophy type 2 (DM2) is a neurogenerative disease caused by caprylic/capric triglyceride (CCTG) tetranucleotide repeat expansions in intron 1 of the cellular nucleic acid‐binding protein (CNBP) gene. Non‐B DNA structures formed by CCTG repeats can promote genetic instability, whereas interrupting motifs of NCTG (N = A/T/G) within CCTG repeats help to maintain genomic stability. However, whether the interrupting motifs can affect DNA structures of CCTG repeats remains unclear. Here, we report that four CCTG repeats with an interrupting 3′‐A/T/G residue formed dumbbell structures, whereas a non‐interrupting 3′‐C residue resulted in a multi‐loop structure exhibiting conformational dynamics that may contribute to a higher tendency of escaping from DNA mismatch repair and causing repeat expansions. The results provide new structural insights into the genetic instability of CCTG repeats in DM2. CCTG tetranucleotide repeat expansions in the cellular nucleic acid‐binding protein (CNBP) gene cause myotonic dystrophy type 2. The presence of A/T/GCTG‐interrupting motif(s) helps to maintain the genomic stability of caprylic/capric triglyceride (CCTG) repeats. Our nuclear magnetic resonance study shows that four CCTG repeats with an interrupting 3′‐A/T/G residue formed dumbbell structures, whereas a non‐interrupting 3′‐C residue resulted in a multi‐loop structure that may have a higher tendency of causing repeat expansions.