Abstract
CAG repeats form stable hairpin structures, which are believed to be responsible for CAG repeat expansions associated with certain human neurological diseases. Human cells possess an accurate DNA hairpin repair system that prevents expansion of disease-associated CAG repeats. Based on transgenic animal studies, it is suggested that (CAG)(n) expansion is caused by abnormal binding of the MutSbeta mismatch recognition protein to (CAG)(n) hairpins, leading to hijacking mismatch repair function during (CAG)(n) hairpin repair. We demonstrate here that MutSbeta displays identical biochemical and biophysical activities (including ATP-provoked conformational change, ATPase, ATP binding, and ADP binding) when interacting with a (CAG)(n) hairpin and a mismatch. More importantly, our in vitro functional hairpin repair assays reveal that excess MutSbeta does not inhibit (CAG)(n) hairpin repair in HeLa nuclear extracts. Evidence presented here provides a novel view as to whether or not MutSbeta is involved in CAG repeat instability in humans.
Highlights
Expansion of trinucleotide repeats (TNRs)3 causes hereditary neurological disorders such as Huntington disease and myotonic dystrophy, whose clinical symptoms are directly linked to expansion of containing a (CAG) and CTG repeats, respectively [1,2,3]
MutS Does Not Inhibit CAG/CTG Hairpin Repair—Repair of DNA hairpins formed within CAG and CTG TNRs has recently been characterized in human cells [6, 7]
The results presented here demonstrate that MutS exhibits identical biochemical and biophysical activities, including nucleotide binding and hydrolysis (Fig. 3), and ATP-induced conformational change and protein translocation/sliding when MutS interacts with its favored ID mispair or a CAG/CTG hairpin (Fig. 2B)
Summary
Mismatch Recognition Protein MutS Does Not Hijack (CAG)n Hairpin Repair in Vitro*□S. Human cells possess an accurate DNA hairpin repair system that prevents expansion of disease-associated CAG repeats. Recent studies have identified and characterized a DNA hairpin repair (HPR) system in human cells that promotes CAG/ CTG repeat stability [6, 7]. It is hypothesized that (CAG)n hairpins, through their ability to alter the biochemical properties of MutS, hijack the MMR process, leading to CAG repeat expansion instead of CAG hairpin removal [11]. It is not clear why MMR, a major genome maintenance system, would promote TNR instability instead of TNR stability. The observations presented here provide novel thoughts on whether or not or how MutS is involved in CAG repeat instability in human cells
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