SRS2 and SGS1 prevent chromosomal breaks and stabilize triplet repeats by restraining recombination

Kerrest, Alix; Anand, R.; Sundararajan, Rangapriya; Bermejo, Rodrigo; Liberi, Giordano; Dujon, Bernard; Freudenreich, Catherine H.; Richard, G

doi:10.1038/nsmb.1544

Cited by 88 publications

(177 citation statements)

References 60 publications

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“…Increasing evidence suggests that hairpin formation occurs via DNA strand slippage during DNA metabolic processes that introduce DNA strand breaks within or near the repeat region (3,4,11). These processes include DNA replication (10,12,13), repair (2,14,15) and recombination (16,17). In addition to DNA strand breaks, which provide opportunities for strand slippage, these processes share a common feature in DNA synthesis, a reaction catalyzed by DNA polymerases.…”

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confidence: 99%

Coordinated Processing of 3′ Slipped (CAG)n/(CTG)n Hairpins by DNA Polymerases β and δ Preferentially Induces Repeat Expansions

Chan

Guo

Zhang

et al. 2013

Journal of Biological Chemistry

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Background: Expansion of CAG/CTG repeats causes familial neurological disorders, but the molecular basis is unknown. Results: DNA polymerases ␤ and ␦ effectively incorporate nucleotides to a CAG/CTG hairpin primer, leading to hairpin retention. Conclusion: Coordinated actions by polymerases ␤ and ␦ on hairpin primers during DNA synthesis promotes CAG/CTG repeat expansions. Significance: The work discovers a novel mechanism for CAG/CTG repeat expansions.

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confidence: 99%

Coordinated Processing of 3′ Slipped (CAG)n/(CTG)n Hairpins by DNA Polymerases β and δ Preferentially Induces Repeat Expansions

Chan

Guo

Zhang

et al. 2013

Journal of Biological Chemistry

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“…CAG·CTG TNRs can expand and contract in length via replicative and nonreplicative mechanisms that have been studied extensively in Escherichia coli, yeast, cultured mammalian cells, and mice (2,3). Furthermore, studies in yeast have suggested that these repeated sequences are sites of DNA double-strand breakage and this has been compared with chromosome fragility (4,5). Recently, interplay between DNA breakage and instability of CAG·CTG TNRs has been suggested with models involving DNA ends generated via replication fork reversal (RFR) (5,6).…”

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confidence: 99%

“…Furthermore, studies in yeast have suggested that these repeated sequences are sites of DNA double-strand breakage and this has been compared with chromosome fragility (4,5). Recently, interplay between DNA breakage and instability of CAG·CTG TNRs has been suggested with models involving DNA ends generated via replication fork reversal (RFR) (5,6). It is therefore critical to establish whether CAG·CTG TNRs are sites of DSB formation via chromosome breakage or RFR, using the model systems available.…”

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confidence: 99%

“…Folate-sensitive rare fragile sites correspond to CCG·CGG TNRs, whereas folate-insensitive rare sites correspond to AT-rich repeats. In Saccharomyces cerevisiae model systems, CAG·CTG and GAA·TTC TNRs have also been shown to be fragile, both directly via the observation of DNA double-strand breaks and via their stimulation of chromosome rearrangements (4,5,9).…”

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confidence: 99%

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DNA tandem repeat instability in the Escherichia coli chromosome is stimulated by mismatch repair at an adjacent CAG·CTG trinucleotide repeat

Blackwood

Okely²,

Zahra³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Approximately half the human genome is composed of repetitive DNA sequences classified into microsatellites, minisatellites, tandem repeats, and dispersed repeats. These repetitive sequences have coevolved within the genome but little is known about their potential interactions. Trinucleotide repeats (TNRs) are a subclass of microsatellites that are implicated in human disease. Expansion of CAG·CTG TNRs is responsible for Huntington disease, myotonic dystrophy, and a number of spinocerebellar ataxias. In yeast DNA double-strand break (DSB) formation has been proposed to be associated with instability and chromosome fragility at these sites and replication fork reversal (RFR) to be involved either in promoting or in preventing instability. However, the molecular basis for chromosome fragility of repetitive DNA remains poorly understood. Here we show that a CAG·CTG TNR array stimulates instability at a 275-bp tandem repeat located 6.3 kb away on the Escherichia coli chromosome. Remarkably, this stimulation is independent of both DNA double-strand break repair (DSBR) and RFR but is dependent on a functional mismatch repair (MMR) system. Our results provide a demonstration, in a simple model system, that MMR at one type of repetitive DNA has the potential to influence the stability of another. Furthermore, the mechanism of this stimulation places a limit on the universality of DSBR or RFR models of instability and chromosome fragility at CAG·CTG TNR sequences. Instead, our data suggest that explanations of chromosome fragility should encompass the possibility of chromosome gaps formed during MMR.DNA repair | DNA replication | fragile site

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“…Our data suggest that in the wild- type strain with an intact Tof1/Csm3/Mrc1 complex, template switching within the (ATTCT) n repeat is a rare event (Table 1). We suggest that fork reversal caused by either an AT-richness or a slippery nature of this repeat is more common, as was also observed for other expandable repeats (32,33). In this scenario (Fig.…”

Section: Discussionmentioning

confidence: 83%

Expansions, contractions, and fragility of the spinocerebellar ataxia type 10 pentanucleotide repeat in yeast

Cherng

Shishkin

Schlager

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Spinocerebellar ataxia 10 (SCA10) is an autosomal dominant disease caused by large-scale expansions of the (ATTCT) n repeat within an intron of the human ATXN10 gene. In contrast to other expandable repeats, this pentanucleotide repeat does not form stable intra-or interstranded DNA structures, being a DNA unwinding element instead. We analyzed the instability of the (ATTCT) n repeat in a yeast experimental system, where its expansions led to inactivation of the URA3 reporter gene. The inactivation was due to a dramatic decrease in the mRNA levels owing to premature transcription termination and RNA polyadenylation at the repeat. The rates of expansions strongly increased with the repeat's length, mimicking genetic anticipation in human pedigrees. A first round of genetic analysis showed that a functional TOF1 gene precludes, whereas a functional RAD5 gene promotes, expansions of the (ATTCT) n repeat. We hypothesize that repeat expansions could occur upon fortuitous template switching during DNA replication. The rate of repeat contractions was elevated in the Tof1 knockout strain, but it was not affected by the RAD5 gene. Supporting the notion of replication irregularities, we found that (ATTCT) n repeats also cause length-dependent chromosomal fragility in yeast. Repeat-mediated fragility was also affected by the Tof1 and Rad5 proteins, being reduced in their absence.DNA repeats | genome instability | DNA repair

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SRS2 and SGS1 prevent chromosomal breaks and stabilize triplet repeats by restraining recombination

Cited by 88 publications

References 60 publications

Coordinated Processing of 3′ Slipped (CAG)n/(CTG)n Hairpins by DNA Polymerases β and δ Preferentially Induces Repeat Expansions

Coordinated Processing of 3′ Slipped (CAG)n/(CTG)n Hairpins by DNA Polymerases β and δ Preferentially Induces Repeat Expansions

DNA tandem repeat instability in the Escherichia coli chromosome is stimulated by mismatch repair at an adjacent CAG·CTG trinucleotide repeat

Expansions, contractions, and fragility of the spinocerebellar ataxia type 10 pentanucleotide repeat in yeast

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