Role of recombination and replication fork restart in repeat instability

Polleys, Erica J; House, Nealia C.M.; Freudenreich, Catherine H.

doi:10.1016/j.dnarep.2017.06.018

Cited by 47 publications

(58 citation statements)

References 137 publications

(188 reference statements)

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“…The repetitive nature of these genomic regions burden normal cell mechanisms such as replication and transcription, leading to an increase in DNA breaks in repeats (Krasilnikova & Mirkin, ; Zhang et al., ). The mechanisms responsible for DNA break‐repair have been largely associated with repeat size instability (Axford et al., ; Gomes‐Pereira et al., ; Lee et al., ; Polleys, House, & Freudenreich, ) and may have had a role in the highly polymorphic nature of this pentanucleotide repeat.…”

Section: Discussionmentioning

confidence: 99%

Mutational mechanism for DAB1 (ATTTC) _n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

et al. 2019

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Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n. Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT‐rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process.

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Section: Discussionmentioning

confidence: 99%

Mutational mechanism for DAB1 (ATTTC) _n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

et al. 2019

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“…Secondary structures could also form during fork reversal ( Figure 1A), leading to either repeat length changes or fork breakage if they inhibit fork restart (reviewed in Refs. 10,11).…”

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The role of fork stalling and DNA structures in causing chromosome fragility

Kaushal

Freudenreich

2019

Genes Chromosomes & Cancer

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Alternative non‐B form DNA structures, also called secondary structures, can form in certain DNA sequences under conditions that produce single‐stranded DNA, such as during replication, transcription, and repair. Direct links between secondary structure formation, replication fork stalling, and genomic instability have been found for many repeated DNA sequences that cause disease when they expand. Common fragile sites (CFSs) are known to be AT‐rich and break under replication stress, yet the molecular basis for their fragility is still being investigated. Over the past several years, new evidence has linked both the formation of secondary structures and transcription to fork stalling and fragility of CFSs. How these two events may synergize to cause fragility and the role of nuclease cleavage at secondary structures in rare and CFSs are discussed here. We also highlight evidence for a new hypothesis that secondary structures at CFSs not only initiate fragility but also inhibit healing, resulting in their characteristic appearance.

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“…Some contractions and expansions were shown to be dependent on DSB repair pathways, including both end-joining and homologous recombination (HR) pathways (29); for review, see ref. 30. However, the initial cause of the breaks at expanded CAG tracts is not known.…”

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confidence: 99%

Cytosine deamination and base excision repair cause R-loop–induced CAG repeat fragility and instability in Saccharomyces cerevisiae

Freudenreich

2017

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

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CAG/CTG repeats are structure-forming repetitive DNA sequences, and expansion beyond a threshold of ∼35 CAG repeats is the cause of several human diseases. Expanded CAG repeats are prone to breakage, and repair of the breaks can cause repeat contractions and expansions. In this study, we found that cotranscriptional R-loops formed at a CAG-70 repeat inserted into a yeast chromosome. R-loops were further elevated upon deletion of yeast RNaseH genes and caused repeat fragility. A significant increase in CAG repeat contractions was also observed, consistent with previous human cell studies. Deletion of yeast cytosine deaminase Fcy1 significantly decreased the rate of CAG repeat fragility and contractions in the rnh1Δrnh201Δ background, indicating that Fcy1-mediated deamination is one cause of breakage and contractions in the presence of R-loops. Furthermore, base excision repair (BER) is responsible for causing CAG repeat contractions downstream of Fcy1, but not fragility. The Rad1/XPF and Rad2/XPG nucleases were also important in protecting against contractions, but through BER rather than nucleotide excision repair. Surprisingly, the MutLγ (Mlh1/Mlh3) endonuclease caused R-loop-dependent CAG fragility, defining an alternative function for this complex. These findings provide evidence that breakage at expanded CAG repeats occurs due to R-loop formation and reveal two mechanisms for CAG repeat instability: one mediated by cytosine deamination of DNA engaged in R-loops and the other by MutLγ cleavage. Since disease-causing CAG repeats occur in transcribed regions, our results suggest that R-loop-mediated fragility is a mechanism that could cause DNA damage and repeatlength changes in human cells.R-loop | CAG repeat instability | chromosome fragility | Fcy1 cytosine deaminase | Mlh1/Mlh3

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Role of recombination and replication fork restart in repeat instability

Cited by 47 publications

References 137 publications

Mutational mechanism for DAB1 (ATTTC) _n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

Mutational mechanism for DAB1 (ATTTC) _n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

The role of fork stalling and DNA structures in causing chromosome fragility

Cytosine deamination and base excision repair cause R-loop–induced CAG repeat fragility and instability in Saccharomyces cerevisiae

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Role of recombination and replication fork restart in repeat instability

Cited by 47 publications

References 137 publications

Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

The role of fork stalling and DNA structures in causing chromosome fragility

Cytosine deamination and base excision repair cause R-loop–induced CAG repeat fragility and instability in Saccharomyces cerevisiae

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Mutational mechanism for DAB1 (ATTTC) _n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

Mutational mechanism for DAB1 (ATTTC) _n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution