DNA Mismatch Repair Complex MutSβ Promotes GAA·TTC Repeat Expansion in Human Cells

Halabi, Anasheh; Ditch, Scott; Wang, Jeffrey; Grabczyk, Ed

doi:10.1074/jbc.m112.356758

Cited by 60 publications

(79 citation statements)

References 71 publications

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“…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 2012;Halabi et al 2012). We recently demonstrated a significant decrease in expansion of both CAG and CTG repeat tracts in Saccharomyces cerevisiae in an msh3D background (Kantartzis et al 2012).…”

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confidence: 77%

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

Williams

Surtees

2015

Genetics

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Trinucleotide repeat (TNR) expansions are the underlying cause of more than 40 neurodegenerative and neuromuscular diseases, including myotonic dystrophy and Huntington's disease, yet the pathway to expansion remains poorly understood. An important step in expansion is the shift from a stable TNR sequence to an unstable, expanding tract, which is thought to occur once a TNR attains a threshold length. Modeling of human data has indicated that TNR tracts are increasingly likely to expand as they increase in size and to do so in increments that are smaller than the repeat itself, but this has not been tested experimentally. Genetic work has implicated the mismatch repair factor MSH3 in promoting expansions. Using Saccharomyces cerevisiae as a model for CAG and CTG tract dynamics, we examined individual threshold-length TNR tracts in vivo over time in MSH3 and msh3D backgrounds. We demonstrate, for the first time, that these TNR tracts are highly dynamic. Furthermore, we establish that once such a tract has expanded by even a few repeat units, it is significantly more likely to expand again. Finally, we show that threshold-length TNR sequences readily accumulate net incremental expansions over time through a series of small expansion and contraction events. Importantly, the tracts were substantially stabilized in the msh3D background, with a bias toward contractions, indicating that Msh2-Msh3 plays an important role in shifting the expansioncontraction equilibrium toward expansion in the early stages of TNR tract expansion.KEYWORDS Saccharomyces cerevisiae; Msh2-Msh3; mismatch repair; trinucleotide repeat tract T HE 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...

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confidence: 77%

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

Williams

Surtees

2015

Genetics

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“…Even in the case of FRDA in which none of the MutS components seem to play a role in intergenerational expansion in the transgenic mouse model (Ezzatizadeh et al ., 2012), loss of either of the MutSα components reduces somatic expansions (Bourn et al ., 2012). Furthermore, knockdown of MutSα reduces expansions of the endogenous FRDA allele in patient derived induced pluripotent stem cells (iPSCs) (Du et al ., 2012; Ku et al ., 2010) and expression of MutSβ promotes GAA expansions in a human kidney cell line (Halabi et al ., 2012). Thus far FRDA appears to be unique in the contribution of MutSα along with MutSβ to expansion.…”

Section: The Role Of Mismatch Repair Proteins In Repeat Instabilitymentioning

confidence: 99%

Repeat instability during DNA repair: Insights from model systems

Usdin

House

Freudenreich

2015

Critical Reviews in Biochemistry and Molecular Biology

164

218

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The expansion of repeated sequences is the cause of over 30 inherited genetic diseases, including Huntington disease, myotonic dystrophy (types 1 and 2), fragile X syndrome, many spinocerebellar ataxias, and some cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions are dynamic, and disease inheritance and progression are influenced by the size and the rate of expansion. Thus, an understanding of the various cellular mechanisms that cooperate to control or promote repeat expansions is of interest to human health. In addition, the study of repeat expansion and contraction mechanisms has provided insight into how repair pathways operate in the context of structure-forming DNA, as well as insights into non-canonical roles for repair proteins. Here we review the mechanisms of repeat instability, with a special emphasis on the knowledge gained from the various model systems that have been developed to study this topic. We cover the repair pathways and proteins that operate to maintain genome stability, or in some cases cause instability, and the cross-talk and interactions between them.

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“…However, MSH6, and thus MutSα has been suggested to promote somatic expansions in an FRDA mouse model [69]. The effect of knockdown of MSH6 in induced pluripotent stem cells derived from FRDA patients [70] and overexpression of MutSβ in a human tissue culture model [71] also supports a role for these complexes in generating expansions in humans.…”

Section: A Diverse Collection Of Proteins Involved In Dna Repair Amentioning

confidence: 99%

The Repeat Expansion Diseases: The dark side of DNA repair

Zhao

Usdin

2015

DNA Repair

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DNA repair normally protects the genome against mutations that threaten genome integrity and thus cell viability. However, growing evidence suggests that in the case of the Repeat Expansion Diseases, disorders that result from an increase in the size of a disease-specific microsatellite, the disease-causing mutation is actually the result of aberrant DNA repair. A variety of proteins from different DNA repair pathways have thus far been implicated in this process. This review will summarize recent findings from patients and from mouse models of these diseases that shed light on how these pathways may interact to cause repeat expansion.

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DNA Mismatch Repair Complex MutSβ Promotes GAA·TTC Repeat Expansion in Human Cells

Cited by 60 publications

References 71 publications

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

Repeat instability during DNA repair: Insights from model systems

The Repeat Expansion Diseases: The dark side of DNA repair

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