Interconverting Conformations of Slipped-DNA Junctions Formed by Trinucleotide Repeats Affect Repair Outcome

Abstract

Expansions of (CTG)·(CAG) repeated DNAs are the mutagenic cause of 14 neurological diseases, likely arising through the formation and processing of slipped-strand DNAs. These transient intermediates of repeat length mutations are formed by out-of-register mispairing of repeat units on complementary strands. The three-way slipped-DNA junction, at which the excess repeats slip out from the duplex, is a poorly understood feature common to these mutagenic intermediates. Here, we reveal that slipped junctions can assume a surprising number of interconverting conformations where the strand opposite the slip-out either is fully base paired or has one or two unpaired nucleotides. These unpaired nucleotides can also arise opposite either of the nonslipped junction arms. Junction conformation can affect binding by various structure-specific DNA repair proteins and can also alter correct nick-directed repair levels. Junctions that have the potential to contain unpaired nucleotides are repaired with a significantly higher efficiency than constrained fully paired junctions. Surprisingly, certain junction conformations are aberrantly repaired to expansion mutations: misdirection of repair to the non-nicked strand opposite the slip-out leads to integration of the excess slipped-out repeats rather than their excision. Thus, slipped-junction structure can determine whether repair attempts lead to correction or expansion mutations.

Long-range correlations in the mechanics of small DNA circles under topological stress revealed by multi-scale simulation

“…Wrinkled DNA structures appear transiently in the atomistic simulations, prior to the formation of denaturation bubbles. The DESIGNED sequence, which contains repetitive elements, was uniquely observed to relieve torsional stress through slip defects, which are implicated in genetic diversity in prokaryotes and diseases such as cancer in humans (47). Most strikingly, both the atomistic and coarse-grained DNA simulations show ‘cooperative kinking’, in which defects preferentially occur at opposite sides of the circle due to DNA bending.…”

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

“…This difference is likely related to the propensity of (CNG) n sequences to form secondary structures once they have slipped and are single stranded owing to the inherent complementarity of the C's and G's within the repeat sequence (Castel et al 2010;McMurray 2010) and to the manner in which Msh2-Msh3 interacts with these unique structures (Lang et al 2011). As the tract length increases, the potential complexity of the secondary structure increases (Gacy and McMurray 1998;Pearson and Sinden 1998;Slean et al 2013). Nonetheless, loss of MSH2 or MSH3 leads to a significant decrease in expansion events in mouse models of HD (Manley et al 1999; Owen et al 2005) and MD1 (van den Broek et al 2002;Foiry et al 2006).…”

The CAA Repeat Polymorphism in the <i>ZFHX3</i> Gene Is Associated with Risk of Coronary Heart Disease in a Chinese Population

“…A survey of the human genome reference sequence revealed that it harbors more than 32,000 tracts of trinucleotide repeat sequences composed of six or more repeated units (Axford et al 2013). In human exons, which account for less than 3% of the genomic sequence, there are as many as 1,030 trinucleotiderepeat tracts (Slean et al 2013). Polymorphic trinucleotide repeats are better tolerated than dinucleotide and tetranucleotide repeats in translated sequences because their length variation does not change the open reading frame (Panigrahi et al 2012).…”