The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair

Oers, Johanna M.M. van; Edwards, YH; Chahwan, Richard; Zhang, W; Smith, Conrad; Pechuan-Jorge, Ximo; Schaetzlein, Sonja; Jin, Bo; Wang, Yuxun; Bergman, Aviv; Scharff, Matthew D.; Edelmann, Winfried

doi:10.1038/onc.2013.365

Cited by 40 publications

(34 citation statements)

References 51 publications

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“…Loss of MSH3 leads to a decrease in expansion events and promotes contractions. However, disruption of Msh2-Msh3 will have a negative impact on overall genome stability; in addition to MMR, Msh2-Msh3 has been implicated in DSBR (Surtees et al 2004;Park et al 2013;van Oers et al 2013) and interstrand DNA cross-link repair (Takahashi et al 2011;Barber et al 2005;Zhao et al 2009). Notably, many neuronally expressed genes contain repetitive sequences in their regulatory regions (Bacolla et al 2008), the stability of which is likely at least partially dependent on Msh2-Msh3.…”

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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Section: Discussionmentioning

confidence: 99%

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

Williams

Surtees

2015

Genetics

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“…In response to ionizing radiation, G2/M checkpoint activation in Msh2 À/À cells is inefficient, such that the cells arrest only transiently before progressing into mitosis (Franchitto et al, 2003). More recently, it has been shown that Msh2 À/À and Msh3 À/À , but not Msh6 À/À , mouse embryonic fibroblasts display a significant increase in chromatid breaks compared to wild-type cells, indicating a defect in DSB repair due to loss of MutSb function (van Oers et al, 2014). However, the role of MutSb in the cellular response to DSBs remains largely uncharacterized.…”

Section: Introductionmentioning

confidence: 97%

The Mismatch-Binding Factor MutSβ Can Mediate ATR Activation in Response to DNA Double-Strand Breaks

et al. 2015

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Ataxia telangiectasia-mutated and Rad3-related (ATR) protein kinase, a master regulator of DNA-damage response, is activated by RPA-coated single-stranded DNA (ssDNA) generated at stalled replication forks or DNA double-strand breaks (DSBs). Here, we identify the mismatch-binding protein MutSβ, a heterodimer of MSH2 and MSH3, as a key player in this process. MSH2 and MSH3 form a complex with ATR and its regulatory partner ATRIP, and their depletion compromises the formation of ATRIP foci and phosphorylation of ATR substrates in cells responding to replication-associated DSBs. Purified MutSβ binds to hairpin loop structures that persist in RPA-ssDNA complexes and promotes ATRIP recruitment. Mutations in the mismatch-binding domain of MSH3 abolish the binding of MutSβ to DNA hairpin loops and its ability to promote ATR activation by ssDNA. These results suggest that hairpin loops might form in ssDNA generated at sites of DNA damage and trigger ATR activation in a process mediated by MutSβ.

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“…1-4 ). There is accumulating circumstantial evidence suggesting a role for the MSH2-MSH3 complex in DSB repair (39)(40)(41)(42)(43). For instance, RNAi-mediated MSH3 depletion has recently been shown to result in substantially delayed RAD51 loading after 2-Gy ionizing radiation ( 25 ).…”

Section: Alterations In Homologous Recombination Signaling Are Associmentioning

confidence: 99%

A Functional Cancer Genomics Screen Identifies a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC

et al. 2014

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Here, we use a large-scale cell line-based approach to identify cancer cell-specifi c mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profi led the mutational landscape across 1,319 cancerassociated genes of 67 distinct cell lines and identifi ed numerous genes involved in homologous recombination-mediated DNA repair, including BRCA1 , BRCA2 , ATM , PAXIP , and RAD50 , as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3 , which have been reported to occur recurrently in numerous human cancer entities, emerged as the most signifi cant predictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3 -mutant cell lines in vitro and displayed remarkable single-agent effi cacy against MSH3 -mutant tumors in vivo . Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects. SIGNIFICANCE:We associate mutations in the MSH3 gene, which are frequently detected in microsatellite-instable colon cancer (∼40%), with a therapeutic response to specifi c DNA-PKcs inhibitors. Because potent DNA-PKcs inhibitors are currently entering early clinical trials, we offer a novel opportunity to genetically stratify patients who may benefi t from a DNA-PKcs-inhibitory therapy. Cancer Discov; 4(5);[592][593][594][595][596][597][598][599][600][601][602][603][604][605]

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The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair

Cited by 40 publications

References 51 publications

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

The Mismatch-Binding Factor MutSβ Can Mediate ATR Activation in Response to DNA Double-Strand Breaks

A Functional Cancer Genomics Screen Identifies a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC

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