Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops

Lang, Walter H.; Coats, Julie; Majka, Jerzy; Hura, Greg L.; Lin, Yuyen; Rasnik, Ivan; McMurray, Cynthia T.

doi:10.1073/pnas.1105461108

Cited by 62 publications

(90 citation statements)

References 45 publications

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“…It was subsequently suggested that the Msh2-Msh3 complex binds CAG hairpins, inhibiting Msh3 ATPase activity and slowing down release of the complex from the hairpin [24], although this last point is still controversial [25]. It was subsequently shown that the human MSH2-MSH3 complex discriminates between repair-competent loops and repairresistant loops, such as those formed by long CAG repeats [26]. More recently, it was shown that short CAG/CTG slip-out structures were efficiently repaired by human MutL and MutS complexes [27,28], and to a lesser extent by MutS [27].…”

Section: Introductionmentioning

confidence: 99%

Replication stalling and heteroduplex formation within CAG/CTG trinucleotide repeats by mismatch repair

et al. 2016

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2 Highlights-CAG/CTG triplet repeats block replication in both orientations on a yeast chromosome -Replication fork stalling depends on mismatch repair integrity -Msh2p is enriched at CAG/CTG triplet repeats in both orientations -MSH2 overexpression favors or stabilizes the formation of heteroduplex molecules 3 AbstractTrinucleotide repeat expansions are responsible for at least two dozen neurological disorders.Mechanisms leading to these large expansions of repeated DNA are still poorly understood. It was proposed that transient stalling of the replication fork by the repeat tract might trigger slippage of the newly-synthesized strand over its template, leading to expansions or contractions of the triplet repeat. However, such mechanism was never formally proven. Here we show that replication fork pausing and CAG/CTG trinucleotide repeat instability are not linked, stable and unstable repeats exhibiting the same propensity to stall replication forks when integrated in a yeast natural chromosome. We found that replication fork stalling was dependent on the integrity of the mismatch-repair system, especially the Msh2p-Msh6p complex, suggesting that direct interaction of MMR proteins with secondary structures formed by trinucleotide repeats in vivo, triggers replication fork pauses. We also show by chromatin immunoprecipitation that Msh2p is enriched at trinucleotide repeat tracts, in both stable and unstable orientations, this enrichment being dependent on MSH3 and MSH6.Finally, we show that overexpressing MSH2 favors the formation of heteroduplex regions, leading to an increase in contractions and expansions of CAG/CTG repeat tracts during replication, these heteroduplexes being dependent on both MSH3 and MSH6. These heteroduplex regions were not detected when a mutant msh2-E768A gene in which the ATPase domain was mutated was overexpressed. Our results unravel two new roles for mismatch-repair proteins: stabilization of heteroduplex regions and transient blocking of replication forks passing through such repeats. Both roles may involve direct interactions between MMR proteins and secondary structures formed by trinucleotide repeat tracts, although indirect interactions may not be formally excluded.

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Section: Introductionmentioning

confidence: 99%

Replication stalling and heteroduplex formation within CAG/CTG trinucleotide repeats by mismatch repair

et al. 2016

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“…Error occurs through two proposed models; 1) the MutSβ (MSH2 and MSH3 complex) entrapment/hairpin escape model 2) the dysregulated strand directionality model. Both provide attractive arguments for a role of mismatch repair in TNR expansion, as both models propose impaired or dysregulated function of MutS, with the second also accounting for the MutL function [31][32][33]. Taken together, it can be seen why the presence of both slip-strand mispairing and mismatch repair creates a 'perfect genetic storm' , where an error in transcription is introduced and the exact mechanism supposedly responsible for correcting the mutation unwittingly aids in its formation.…”

Section: Mutagenic Mismatch Repairmentioning

confidence: 98%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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“…It has been found that formation of non-B form DNA secondary structures such as hairpins, triplexes and tetraplexes is responsible for TNR expansion and deletion during DNA replication, repair, recombination and gene transcription (4,85,86,140,198,260). The secondary structures formed in a newly synthesized strand or damaged strand of the genome usually result in replication fork stalling (4,107), pausing of DNA polymerases and DNA slippage (4,108), trapping of mismatch repair proteins (113,114), inhibition of flap endonuclease 1 (FEN1) processing of a hairpin (111,167,261) and disruption of coordination among repair enzymes (115), and this ultimately leads to TNR expansion. In contrast, TNR secondary structures formed at the template strand during DNA repair promote DNA polymerases to skip over the structures, and this causes TNR deletion.…”

Section: Discussionmentioning

confidence: 99%

“…If a single-strand DNA breaks occurs during DNA lagging strand maturation and DNA repair, a downstream 5'-TNR-containing flap can fold back and form a hairpin structure that inhibits flap cleavage by FEN1 (110)(111)(112). In addition, a mismatch repair protein complex, MSH2/MSH3 can be trapped by hairpin structures (113,114) and stabilize the hairpin structure promoting TNR instability. Formation of a hairpin structure can also disrupt the coordination among DNA repair proteins that sustains an efficient DNA repair.…”

Section: Tnr Instability and Dna Repairmentioning

confidence: 99%

Oxidative DNA Damage Modulates Trinucleotide Repeat Instability Via DNA Base Excision Repair

Xu¹

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Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops

Cited by 62 publications

References 45 publications

Replication stalling and heteroduplex formation within CAG/CTG trinucleotide repeats by mismatch repair

Replication stalling and heteroduplex formation within CAG/CTG trinucleotide repeats by mismatch repair

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

Oxidative DNA Damage Modulates Trinucleotide Repeat Instability Via DNA Base Excision Repair

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