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Mirkin, Sergei M.; Смирнова, Е В

doi:10.1038/ng0502-5

Cited by 40 publications

(33 citation statements)

References 14 publications

(12 reference statements)

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“…Our results suggest that replication can initiate at or near either of two sites, upstream (IS DMPK ) or downstream (IS SIX5 ) of the (CTG) n · (CAG) n TNRs in non-DM1 cells and in DM1 cells. In 428-12D DM1 lymphoblasts that have lost IS DMPK on the nonexpanded chromosome, (CTG) n is copied as the leading-strand template from IS SIX5 , which is the orientation that preferentially gives rise to expansions (56,67,70). In the GM04033 and GM03987 DM1 cell populations, both IS DMPK and IS SIX5 origins are active.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, prereplication complex (pre-RC) binding sites in the DMPK/SIX 5 region have been identified by chromatin immunoprecipitation (ChIP). In non-DM1 cell populations, DNA replication initiation sites are located on either side of the DMPK TNRs, indicating that the (CAG) n repeats may be used as either a lagging-strand template, favoring TNR expansion, or a leading-strand template, favoring TNR contraction, during DNA replication (67). The presence of two replication origins in the DMPK locus was supported by the detection of the binding sites of the prereplication complex, which revealed that Orc2 and Mcm4 were recruited to two adjacent initiation sites near IS DMPK and IS SIX5 .…”

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confidence: 99%

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Altered Replication in Human Cells Promotes DMPK (CTG)_n · (CAG)_n Repeat Instability

Liu

Chen

Gao

et al. 2012

Molecular and Cellular Biology

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Altered Replication in Human Cells Promotes DMPK (CTG)_n · (CAG)_n Repeat Instability

Liu

Chen

Gao

et al. 2012

Molecular and Cellular Biology

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“…The fork reversal-template switch pathways have also been implicated in instability of repetitive sequences (80,128,140,202). The fact that virtually all of the pathways for replication restart can, under certain circumstances, result in DNA rearrangements makes replication stalling a powerful source of genomic instability (42,43,195,204,255). A growing number of studies show that replication stalling at natural impediments can be a source of genomic instability, such as chromosomal rearrangements, chromosomal fragility, and instability of various repetitive sequences.…”

Section: Genomic Instability Caused By Replication Stalling At Naturamentioning

confidence: 99%

Replication Fork Stalling at Natural Impediments

Mirkin

2007

Microbiol Mol Biol Rev

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452

466

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SUMMARY Accurate and complete replication of the genome in every cell division is a prerequisite of genomic stability. Thus, both prokaryotic and eukaryotic replication forks are extremely precise and robust molecular machines that have evolved to be up to the task. However, it has recently become clear that the replication fork is more of a hurdler than a runner: it must overcome various obstacles present on its way. Such obstacles can be called natural impediments to DNA replication, as opposed to external and genetic factors. Natural impediments to DNA replication are particular DNA binding proteins, unusual secondary structures in DNA, and transcription complexes that occasionally (in eukaryotes) or constantly (in prokaryotes) operate on replicating templates. This review describes the mechanisms and consequences of replication stalling at various natural impediments, with an emphasis on the role of replication stalling in genomic instability.

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“…Rad27 also plays a role in maintaining the stability of telomere repeat sequences (45,46). TNR expansion is now known to be the cause of at least 15 hereditary human neurodegenerative diseases including Huntington's disease, spinocerebellar ataxia, and myotonic dystrophy (40,48). The role of FEN1 in maintaining the integrity of repeated sequences implies that the enzyme may participate in preventing these human diseases.…”

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confidence: 99%

Saccharomyces cerevisiae Flap Endonuclease 1 Uses Flap Equilibration To Maintain Triplet Repeat Stability

Liu

Zhang²,

Veeraraghavan

et al. 2004

Molecular and Cellular Biology

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Flap endonuclease 1 (FEN1) is a central component of Okazaki fragment maturation in eukaryotes.Genetic analysis of Saccharomyces cerevisiae FEN1 (RAD27) also reveals its important role in preventing trinucleotide repeat (TNR) expansion. In humans such expansion is associated with neurodegenerative diseases. In vitro, FEN1 can inhibit TNR expansion by employing its endonuclease activity to compete with DNA ligase I. Here we employed two yeast FEN1 nuclease mutants, rad27-G67S and rad27-G240D, to further define the mechanism by which FEN1 prevents TNR expansion. Using a yeast artificial chromosome system that can detect both TNR instability and fragility, we demonstrate that the G240D but not the G67S mutation increases both the expansion and fragility of a CTG tract in vivo. In vitro, the G240D nuclease is proficient in cleaving a fixed nonrepeat double flap; however, it exhibits severely impaired cleavage of both nonrepeat and CTG-containing equilibrating flaps. In contrast, wild-type FEN1 and the G67S mutant exhibit more efficient cleavage on an equilibrating flap than on a fixed CTG flap. The degree of TNR expansion and the amount of chromosome fragility observed in the mutant strains correlate with the severity of defective flap cleavage in vitro. We present a model to explain how flap equilibration and the unique tracking mechanism of FEN1 can collaborate to remove TNR flaps and prevent repeat expansion.Eukaryotic flap endonuclease 1 (FEN1) is critical for removing initiator RNA primers from Okazaki fragments during DNA lagging-strand synthesis (20,50,60). The enzyme belongs to a highly conserved 5Ј endo-exonuclease superfamily (53). FEN1 is a structure-specific nuclease in that it specifically removes the 5Ј unannealed flap in a branch structure resulting from strand displacement synthesis. This property allows the enzyme to actively participate in both Okazaki fragment processing and DNA long-patch base excision repair (12, 37) since both of these processes involve creation of a 5Ј flap by strand displacement synthesis. The removal of initiator RNA primers in Okazaki fragments has been proposed as a two-step mechanism in which an endonuclease, Dna2 protein, removes a part of the flap (2). The remainder of the flap is then cut off by FEN1, leaving a nick to be ligated. Other studies suggest that FEN1 alone is sufficient for removal of most flaps (1). Studies in vivo demonstrate a critical role for FEN1 since the absence of enzyme activity in mice leads to embryonic lethality (30). Knocking out one copy of FEN1 along with one of the adenomatous polyposis coli genes in mice results in an increased number of adenocarcinomas, presumably due to the partial loss of FEN1 function in mammalian DNA replication and repair (30).In Saccharomyces cerevisiae the FEN1 homologue, RAD27/ RTH1 (47) demonstrates a high homology (79% conserved and 60% identical) with human FEN1 (53). A deletion of RAD27/ RTH1 leads to conditional lethality phenotypes (54). The mutant cells exhibit temperature sensitivity and cell cycle arrest ...

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Cited by 40 publications

References 14 publications

Altered Replication in Human Cells Promotes DMPK (CTG)_n · (CAG)_n Repeat Instability

Altered Replication in Human Cells Promotes DMPK (CTG)_n · (CAG)_n Repeat Instability

Replication Fork Stalling at Natural Impediments

Saccharomyces cerevisiae Flap Endonuclease 1 Uses Flap Equilibration To Maintain Triplet Repeat Stability

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Positioned to expand

Cited by 40 publications

References 14 publications

Altered Replication in Human Cells Promotes DMPK (CTG)n · (CAG)n Repeat Instability

Altered Replication in Human Cells Promotes DMPK (CTG)n · (CAG)n Repeat Instability

Replication Fork Stalling at Natural Impediments

Saccharomyces cerevisiae Flap Endonuclease 1 Uses Flap Equilibration To Maintain Triplet Repeat Stability

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Product

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Altered Replication in Human Cells Promotes DMPK (CTG)_n · (CAG)_n Repeat Instability

Altered Replication in Human Cells Promotes DMPK (CTG)_n · (CAG)_n Repeat Instability