Histone Deacetylase Complexes Promote Trinucleotide Repeat Expansions

Debacker, Kim; Frizzell, Aisling; Gleeson, Olive; Kirkham-McCarthy, Lucy; Mertz, Tony M.; Lahue, Robert S.

doi:10.1371/journal.pbio.1001257

Cited by 59 publications

(107 citation statements)

References 47 publications

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“…1D); therefore this HDAC is not involved in protection against CAG expansions. Interestingly, loss of Rpd3 did lead to a significant decrease in contraction frequency (Table S1), similar to the suppression of (CAG) 20 expansions observed after Rpd3L knockdown, which was attributed to stabilization of the Sae2 nuclease (Debacker et al, 2012). Hda1 also targets both histone H3 and the Sae2 nuclease (Robert et al, 2011), and we showed previously that Sae2 is required to prevent (CAG) 70 expansions (Sundararajan et al, 2010).…”

Section: Resultssupporting

confidence: 61%

NuA4 Initiates Dynamic Histone H4 Acetylation to Promote High-Fidelity Sister Chromatid Recombination at Postreplication Gaps

et al. 2014

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Summary CAG/CTG trinucleotide repeats are unstable, fragile sequences that strongly position nucleosomes, but little is known about chromatin modifications required to prevent genomic instability at these or other structure-forming sequences. We discovered that regulated histone H4 acetylation is required to maintain CAG repeat stability and promote gap-induced sister chromatid recombination. CAG expansions in the absence of H4 HATs NuA4 and Hat1 and HDACs Sir2, Hos2, Hst1 depended on Rad52, Rad57, and Rad5, and were therefore arising through homology-mediated post-replication repair (PRR) events. H4K12 and H4K16 acetylation were required to prevent Rad5-dependent CAG repeat expansions, and H4K16 acetylation was enriched at CAG repeats during S-phase. Genetic experiments placed the RSC chromatin remodeler in the same PRR pathway, and Rsc2 recruitment was coincident with H4K16 acetylation. Here we have utilized a repetitive DNA sequence that induces endogenous DNA damage to identify histone modifications that regulate recombination efficiency and fidelity during post-replication gap-repair.

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Section: Resultssupporting

confidence: 61%

NuA4 Initiates Dynamic Histone H4 Acetylation to Promote High-Fidelity Sister Chromatid Recombination at Postreplication Gaps

et al. 2014

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“…It is important to note that Msh2-Msh3-mediated expansions are just one mechanism by which TNR tracts increase in length. This yeast system is amenable to examining the contribution of additional genetic factors on tract dynamics in both deletion and mutation backgrounds (e.g., Debacker et al 2012;Concannon and Lahue 2014)). …”

Section: Discussionmentioning

confidence: 99%

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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“…Recently, it has been reported that histone deacetylase complexes promote instability in threshold size (CAG⅐CTG) 20 repeats in budding yeast and human astrocytes. HDAC inhibitors targeting those complexes strongly reduced the propensity of the (CAG⅐ CTG) 20 repeats to expand (70). If this effect translates to the longer GAA⅐TTC repeats in FRDA, then the HDAC inhibitors currently being studied as potential FRDA therapeutics may serve double duty by: 1) increasing transcription through the repeat and 2) suppressing further expansion.…”

Section: Discussionmentioning

confidence: 99%

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

Halabi

Ditch²,

Wang

et al. 2012

Journal of Biological Chemistry

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Background: Friedreich ataxia (FRDA) is a progressive, debilitating and lethal disease caused by GAA⅐TTC repeat expansion. Results: Expression of mismatch repair complex MutS␤, particularly the MSH3 subunit, is necessary for GAA⅐TTC repeat expansion in model cells and FRDA patient fibroblasts. Conclusion: MutS␤ promotes GAA⅐TTC expansion in FRDA. Significance: MSH3 may be a potential therapeutic target for slowing GAA⅐TTC expansion.

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Histone Deacetylase Complexes Promote Trinucleotide Repeat Expansions

Abstract: Genetic analysis in budding yeast and in cultured human astrocytes reveals that specific histone deacetylase complexes accelerate expansion mutations in DNA triplet repeats.

Cited by 59 publications

References 47 publications

NuA4 Initiates Dynamic Histone H4 Acetylation to Promote High-Fidelity Sister Chromatid Recombination at Postreplication Gaps

NuA4 Initiates Dynamic Histone H4 Acetylation to Promote High-Fidelity Sister Chromatid Recombination at Postreplication Gaps

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

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

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