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

Viterbo, David; Michoud, Grégoire; Mosbach, Valentine; Dujon, Bernard; Richard, Guy‐Franck

doi:10.1016/j.dnarep.2016.03.002

Cited by 37 publications

(59 citation statements)

References 74 publications

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“…In the current study using a longer (CTG) 98 repeat, we were able to see a more distinct pause signal in wild-type cells, showing that expanded CAG/CTG repeats on a eukaryotic chromosome pause replication, consistent with other recent results (57). Even though the pausing signal was reduced overall in the srs2 mutants compared to wild-type (Supplementary Table S4) it is still visible in some cases, indicating that the pause is not dependent on the presence of the full-length Srs2 protein.…”

Section: Discussionsupporting

confidence: 93%

“…We conclude that (CTG) 98 repeats stall forks more efficiently than (CTG) 55 repeats, likely because this longer repeat tract has a higher probability of hairpin structure formation. Interestingly, the JMs are somewhat less prominent for the CTG 98 tract compared to (CTG) 55 , suggesting there could be an inverse relationship between a stable fork stall and JMs, a conclusion also reached in a recent study (57). …”

Section: Resultssupporting

confidence: 64%

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Differential requirement of Srs2 helicase and Rad51 displacement activities in replication of hairpin-forming CAG/CTG repeats

Nguyen¹,

Viterbo²,

Anand³

et al. 2017

Nucleic Acids Research

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Trinucleotide repeats are a source of genome instability, causing replication fork stalling, chromosome fragility, and impaired repair. Specialized helicases play an important role in unwinding DNA structures to maintain genome stability. The Srs2 helicase unwinds DNA hairpins, facilitates replication, and prevents repeat instability and fragility. However, since Srs2 is a multifunctional protein with helicase activity and the ability to displace Rad51 recombinase, it was unclear which functions were required for its various protective roles. Here, using SRS2 separation-of-function alleles, we show that in the absence of Srs2 recruitment to PCNA or in helicase-deficient mutants, breakage at a CAG/CTG repeat increases. We conclude that Srs2 interaction with PCNA allows the helicase activity to unwind fork-blocking CAG/CTG hairpin structures to prevent breaks. Independently of PCNA binding, Srs2 also displaces Rad51 from nascent strands to prevent recombination-dependent repeat expansions and contractions. By 2D gel electrophoresis, we detect two different kinds of structured intermediates or joint molecules (JMs). Some JMs are Rad51-independent and exhibit properties of reversed forks, including being processed by the Exo1 nuclease. In addition, in a helicase-deficient mutant, Rad51-dependent JMs are detected, probably corresponding to recombination between sisters. These results clarify the many roles of Srs2 in facilitating replication through fork-blocking hairpin lesions.

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Section: Discussionsupporting

confidence: 93%

Section: Resultssupporting

confidence: 64%

Differential requirement of Srs2 helicase and Rad51 displacement activities in replication of hairpin-forming CAG/CTG repeats

Nguyen¹,

Viterbo²,

Anand³

et al. 2017

Nucleic Acids Research

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“…GAA/TCC triplexes and GGC/CCG repeats strongly interfere with replication progression, acting as site-specific barriers (20–22). CAG/CTG repeats are much weaker barriers (23–26) but their replication generates joint molecules that likely represent both reversed fork and sister chromatid recombination intermediates (27, 28). Single stranded gaps occur when leading and lagging strand synthesis becomes uncoupled (reviewed in (29)), and pre-existing DNA nicks or gaps can become DSBs if replicated (5, 30, 31).…”

Section: Recombination During Replication Results In Repeat Instabilitymentioning

confidence: 99%

Role of recombination and replication fork restart in repeat instability

2017

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Eukaryotic genomes contain many repetitive DNA sequences that exhibit size instability. Some repeat elements have the added complication of being able to form secondary structures, such as hairpin loops, slipped DNA, triplex DNA or G-quadruplexes. Especially when repeat sequences are long, these DNA structures can form a significant impediment to DNA replication and repair, leading to DNA nicks, gaps, and breaks. In turn, repair or replication fork restart attempts within the repeat DNA can lead to addition or removal of repeat elements, which can sometimes lead to disease. One important DNA repair mechanism to maintain genomic integrity is recombination. Though early studies dismissed recombination as a mechanism driving repeat expansion and instability, recent results indicate that mitotic recombination is a key pathway operating within repetitive DNA. The action is two-fold: first, it is an important mechanism to repair nicks, gaps, breaks, or stalled forks to prevent chromosome fragility and protect cell health; second, recombination can cause repeat expansions or contractions, which can be deleterious. In this review, we summarize recent developments that illuminate the role of recombination in maintaining genome stability at DNA repeats.

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“…We believe that large-scale expansions of long CAG tracts are rooted in their ability to form stable hairpin structures during DNA synthesis, which ultimately leads to replication fork stalling 8,24 (Fig. 4A,B).…”

Section: Discussionmentioning

confidence: 99%

The role of break-induced replication in large-scale expansions of (CAG)n/(CTG)n repeats

Kim

Harris

Dinter

et al. 2016

Nat Struct Mol Biol

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Expansions of (CAG)n•(CTG)n trinucleotide repeats are responsible for over a dozen neuromuscular and neurodegenerative disorders. Large-scale expansions are typical for human pedigrees and may be explained by iterative small-scale events such as strand slippage during replication or repair DNA synthesis. Alternatively, a distinct mechanism could lead to a large-scale repeat expansion at a step. To distinguish between these possibilities, we developed a novel experimental system specifically tuned to analyze large-scale expansions of (CAG)n•(CTG)n repeats in Saccharomyces cerevisiae. The median size of repeat expansions was ~60 triplets, though additions in excess of 150 triplets were also observed. Genetic analysis revealed that Rad51, Rad52, Mre11, Pol32, Pif1, and Mus81 and/or Yen1 proteins are required for large-scale expansions, whereas proteins previously implicated in small-scale expansions are not involved. Based on these results, we propose a new model for large-scale expansions based on recovery of replication forks broken at (CAG)n•(CTG)n repeats via break-induced replication.

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

Cited by 37 publications

References 74 publications

Differential requirement of Srs2 helicase and Rad51 displacement activities in replication of hairpin-forming CAG/CTG repeats

Differential requirement of Srs2 helicase and Rad51 displacement activities in replication of hairpin-forming CAG/CTG repeats

Role of recombination and replication fork restart in repeat instability

The role of break-induced replication in large-scale expansions of (CAG)n/(CTG)n repeats

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