Genome-wide high-resolution mapping of chromosome fragile sites in
            <i>Saccharomyces cerevisiae</i>

Song, Wei; Dominska, Margaret; Greenwell, Patricia W.; Petes, Thomas D.

doi:10.1073/pnas.1406847111

Cited by 78 publications

(115 citation statements)

References 53 publications

(71 reference statements)

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“…Most of the statistical tests followed the methods described in our previous studies (10,41). Briefly, χ 2 tests were performed using VassarStat (vassarstats.net) or the chisq.test functions in Excel.…”

Section: Methodsmentioning

confidence: 99%

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Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae

Zheng

Zhang

et al. 2016

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

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DNA replication stress (DRS)-induced genomic instability is an important factor driving cancer development. To understand the mechanisms of DRS-associated genomic instability, we measured the rates of genomic alterations throughout the genome in a yeast strain with lowered expression of the replicative DNA polymerase δ. By a genetic test, we showed that most recombinogenic DNA lesions were introduced during S or G 2 phase, presumably as a consequence of broken replication forks. We observed a high rate of chromosome loss, likely reflecting a reduced capacity of the lowpolymerase strains to repair double-stranded DNA breaks (DSBs). We also observed a high frequency of deletion events within tandemly repeated genes such as the ribosomal RNA genes. By whole-genome sequencing, we found that low levels of DNA polymerase δ elevated mutation rates, both single-base mutations and small insertions/ deletions. Finally, we showed that cells with low levels of DNA polymerase δ tended to accumulate small promoter mutations that increased the expression of this polymerase. These deletions conferred a selective growth advantage to cells, demonstrating that DRS can be one factor driving phenotypic evolution.DNA replication stress | DNA polymerase | genome instability I n normal rapidly dividing cells, DNA replication is rapid and accurate, preventing the accumulation of genomic alterations. Stalling of replication forks or inappropriate initiation of replication origins can result in DNA replication stress (DRS) that can contribute to cancer development (1). It has been proposed that mutations in oncogenes and tumor suppressor genes drive cell proliferation and induce DRS. In turn, DRS generates genome instability, allowing cells with various types of genetic variations (mutations, duplications, translocations) to escape cellular senescence and apoptosis (2). However, the mechanisms by which oncogenes induce DRS and the precise nature of DRSassociated DNA lesions have not been clearly defined.Exposure of mammalian cells in culture to conditions that perturb DNA synthesis result in "fragile sites," gaps or constrictions detected by light microscopy in metaphase chromosomes (3). Aphidicolin, a drug that inhibits DNA polymerase, is one agent that induces fragile sites. The break points of chromosome rearrangements that occur in tumor cells often colocalize with fragile sites (3, 4), establishing another link between DRS and cancer. In addition to inducing chromosome breaks in cultured cells, aphidicolin induces high frequencies of duplications and deletions similar to those observed in tumor cells (5).As a model for mammalian fragile sites, we previously constructed yeast strains in which the transcription of the replicative DNA polymerases α (encoded by POL1) or δ (encoded by POL3) was regulated by the GAL1 promoter (6-8). Under lowgalactose growth conditions, which reduced the levels of DNA polymerases α or δ about 10-fold, these strains had elevated rates of chromosome loss and rearrangements on chromosome III.We also studied g...

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Section: Methodsmentioning

confidence: 99%

“…We applied this method to map events associated with low DNA polymerase α, and showed that LOH events were often associated with chromosome elements [such as quadruplex motifs, termination (ter) sequences, and long-terminal repeats (LTRs)] that slow replication forks (10).…”

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confidence: 99%

Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae

Zheng

Zhang

et al. 2016

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

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“…However, it has also been recognized that HR also has the potential to induce genome instability, acting inappropriately or in an unregulated fashion (Elliott and Jasin 2002;Kolodner et al 2002). For example, ectopic recombination between repeated DNA is a potent driver of chromosomal rearrangements, as suspected from genomic analysis and established in genetic model systems (Szankasi et al 1986;Cooper et al 1997;Agarwal et al 2006;Haber 2006;Weinstock et al 2006;Putnam et al 2009;Song et al 2014). Furthermore, the identification of synthetic lethality in double mutants that depend on HR, called recombination-dependent lethality, shows that uncontrolled HR leads to potentially toxic intermediates and cell death (Heude et al 1995;Schild 1995;Gangloff et al 2000;Fabre et al 2002;Bastin-Shanower et al 2003).…”

Section: Quality Control By Pathway Reversibilitymentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

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“…In previous studies of chromosome rearrangements in yeast strains with low levels of DNA polymerase a (Song et al 2014), we found deletions and duplications in addition to other types of changes. Most of these events were a consequence of homologous recombination between Ty elements or other dispersed repeats.…”

Section: Discussionmentioning

confidence: 53%

“…Although simple nondisjunction events would be expected to produce equal frequencies of trisomies and monosomies, the relative growth rates of trisomic and monosomic strains might skew the ratio of these events. It is unlikely that this factor is completely responsible for our observations, since we previously showed that, in yeast strains with low levels of DNA polymerase a, monosomic strains were five times more frequent than trisomic strains (Song et al 2014).…”

Section: Discussionmentioning

confidence: 79%

The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces cerevisiae

et al. 2015

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Genomic instability is a common feature found in cancer cells . Accordingly, many tumor suppressor genes identified in familiar cancer syndromes are involved in the maintenance of the stability of the genome during every cell division and are commonly referred to as caretakers. Inactivating mutations and epigenetic silencing of caretakers are thought to be the most important mechanisms that explain cancer-related genome instability. However, little is known of whether transient inactivation of caretaker proteins could trigger genome instability and, if so, what types of instability would occur. In this work, we show that a brief and reversible inactivation, during just one cell cycle, of the key phosphatase Cdc14 in the model organism Saccharomyces cerevisiae is enough to result in diploid cells with multiple gross chromosomal rearrangements and changes in ploidy. Interestingly, we observed that such transient loss yields a characteristic fingerprint whereby trisomies are often found in small-sized chromosomes, and gross chromosome rearrangements, often associated with concomitant loss of heterozygosity, are detected mainly on the ribosomal DNAbearing chromosome XII. Taking into account the key role of Cdc14 in preventing anaphase bridges, resetting replication origins, and controlling spindle dynamics in a well-defined window within anaphase, we speculate that the transient loss of Cdc14 activity causes cells to go through a single mitotic catastrophe with irreversible consequences for the genome stability of the progeny. KEYWORDS Cdc14; Saccharomyces cerevisiae; gross chromosomal rearrangements; aneuploidy; caretaker genes G ENOMIC instability is one of the hallmarks of cancer cells. Many genomic alterations result in gene dose variation including deletions/duplication, gross chromosomal rearrangements (GCRs), and aneuploidy; loss of heterozygosity (LOH) associated with mitotic recombination is also observed (Hanahan and Weinberg 2011). In wild-type cells, specialized mechanisms exist, such as cell cycle checkpoints and DNA repair activities, which suppress genome instability. Genes encoding for proteins that protect cells from cancer-related genomic instability are referred to as caretakers. Many of the tumor suppressor genes identified in familiar cancer-prone syndromes are caretakers. Although caretakers are not directly responsible for the decision of a cell to divide, their loss leads cells to rapidly accumulate genomic aberrations and mutations that potentially result in disorganization of cell division and their subsequent transformation into cancer cells (Kinzler and Vogelstein 1997;van Heemst et al. 2007). For example, mutations in genes involved in DNA repair pathways such as nonhomologous end joining, homologous recombination, mismatch repair, base excision repair, and nucleotide excision repair have been shown to lead to the accumulation of mutations within the genome that significantly increase the risk of carcinogenesis (Negrini et al. 2010; Aguilera and García-Muse 2013 protein (BLM) ac...

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Genome-wide high-resolution mapping of chromosome fragile sites in Saccharomyces cerevisiae

Cited by 78 publications

References 53 publications

Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae

Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae

Regulation of Recombination and Genomic Maintenance

The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces cerevisiae

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