title: The origin of genetic instability in CCTG repeats.
abstract: CCTG tetranucleotide repeat expansion is associated with a hereditary neurological disease called myotonic dystrophy type 2 (DM2). The underlying reasons that lead to genetic instability and thus repeat expansion during DNA replication remains elusive. Here, we have shown CCTG repeats have a high propensity to form metastable hairpin and dumbbell structures using high-resolution nuclear magnetic resonance (NMR) spectroscopy. When the repeat length is equal to three, a hairpin with a two-residue CT loop is formed. In addition to the hairpin, a dumbbell structure with two CT-loops is formed when the repeat length is equal to four. Nuclear Overhauser effect (NOE) and chemical shift data reveal both the hairpin and dumbbell structures contain a flexible stem comprising a C-bulge and a T·T mismatch. With the aid of single-site mutation samples, NMR results show these peculiar structures undergo dynamic conformational exchange. In addition to the intrinsic flexibility in the stem region of these structures, the exchange process also serves as an origin of genetic instability that leads to repeat expansion during DNA replication. The structural features provide important drug target information for developing therapeutics to inhibit the expansion process and thus the onset of DM2.
authors.affiliation: Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. lams@cuhk.edu.hk
authors.forename: Sik Lok
authors.initials: SL
authors.lastname: Lam
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.forename: Lai Man
authors.initials: LM
authors.lastname: Chi
mesh_terms: D004247:DNA / Q000737:chemistry; D042622:DNA Repeat Expansion; D018895:Microsatellite Repeats; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation
chemical_list: D004247:DNA