Academic journal article Genetics

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts in Vivo

Academic journal article Genetics

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts in Vivo

Article excerpt

THE EXPANSION of trinucleotide repeat (TNR) sequences is the underlying cause of over 40 neurodegenerative and neuromuscular diseases (Castel et al. 2010; McMurray 2010). TNR sequences made of (CNG)n repeats are of particular interest because of their role in causing Huntington's disease (HD) and myotonic dystrophy type 1 (DM1), as well as a number of other diseases (McMurray 2010). TNR tracts within the normal range (which is tract dependent) are stably maintained within that range (Figure 1). However, through a mechanism(s) that remains unclear, a TNR tract can expand, increasing the number of repeats within the tract. Initially, this brings the tract into a threshold-length range (Gannon et al. 2012; Concannon and Lahue 2014) (Figure 1 and Figure 2), in which these somewhat longer tracts are not pathogenic but are increasingly susceptible to expansion; individuals with this phenomenon are carriers for disease. Once a tract has expanded sufficiently, it crosses a threshold; tracts above this threshold (which is disease specific) are pathogenic and cause disease (Figure 1). As the size of the tract increases, it becomes increasingly unstable and prone to changes in length, particularly expansions.

The dynamic behavior of TNR tracts that are within the threshold range (i.e., more susceptible to expansions) and the manner in which they occur in vivo remain unclear. Studies of TNR tract length changes have largely relied on end point experiments and therefore do not address the dynamic behavior of the tracts, i.e., the rate at which tracts continue to expand. Modeling of human data has predicted that threshold-length TNR tracts will continue to increase in length in increments smaller than the repeat itself (Higham et al. 2012; Morales et al. 2012; Higham and Monckton 2013), although this has never been demonstrated directly. Single-sperm typing studies in humans demonstrated small expansion and contraction events (one-two repeats) in TNR sequences in Kennedy's disease, HD, and DM1 patients (Zhang et al. 1994; Leeflang et al. 1995, 1999; Martorell et al. 2004), particularly in alleles near the pathogenic threshold (Zhang et al. 1994; Leeflang et al. 1995; Castel et al. 2010). These observations are consistent with the existence of an equilibrium between expansion and contraction events. As the tract length increased in sperm cells, there was significant bias toward expansions vs. contractions. The sizes of the observed expansion and contraction events were similar to our in vitro observations (one-two repeats) (Kantartzis et al. 2012), in contrast to larger expansion events observed in nondividing cells or postmitotic neurons (McMurray 2010).

One factor known to contribute to (CNG)n tract expansions is the mismatch repair (MMR) complex Msh2-Msh3 (MutSb in mammals). Typically, Msh2-Msh3 recognizes and binds insertion- deletion loops (IDLs) that result from DNA polymerase slippage events, often within repetitive sequences (Lovett 2004; Li 2008). These are then targeted for excision and resynthesis. Strikingly, rather than correcting them, Msh2- Msh3 promotes TNR expansions in both mammalian somatic and germ cells (Castel et al. 2010; McMurray 2010). 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). Similarly, Msh3 promotes expansions in human cells (Gannon et al. …

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