Mutator genes for suppression of gross chromosomal rearrangements identified by a genome-wide screening in
            <i>Saccharomyces cerevisiae</i>

Smith, Stephanie; Hwang, Ji-Young; Banerjee, Soma; Majeed, Anju; Gupta, Amitabha; Myung, Kyungjaem

doi:10.1073/pnas.0403093101

Cited by 135 publications

(157 citation statements)

References 51 publications

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“…RAD5 deficiency results in higher sensitivity to various types of DNA damage than deletion of either MMS2 or UBC13 [33]. Furthermore, rad5Δ mutants, relative to other PRR mutants, are highly sensitive to ionizing radiation, have elevated rates of spontaneous mitotic recombination, higher rates of gross chromosomal rearrangements, paradoxically increased stability of simple repetitive sequences and higher end-joining activity in a plasmid gap repair [53][54][55][56]. Similar to our findings, Chen et.…”

Section: Discussionsupporting

confidence: 89%

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

et al. 2007

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Replication forks stall at DNA lesions or as a result of an unfavorable replicative environment. These fork stalling events have been associated with recombination and gross chromosomal rearrangements. Recombination and fork bypass pathways are the mechanisms accountable for restart of stalled forks. An important lesion bypass mechanism is the highly conserved postreplication repair (PRR) pathway that is composed of error-prone translesion and error-free bypass branches. EXO1 codes for a Rad2p family member nuclease that has been implicated in a multitude of eukaryotic DNA metabolic pathways that include DNA repair, recombination, replication, and telomere integrity. In this report, we show EXO1 functions in the MMS2 error-free branch of the PRR pathway independent of the role of EXO1 in DNA mismatch repair (MMR). Consistent with the idea that EXO1 functions independently in two separate pathways, we defined a domain of Exo1p required for PRR distinct from those required for interaction with MMR proteins. We then generated a point mutant exo1 allele that was defective for the function of Exo1p in MMR due to disrupted interaction with Mlh1p, but still functional for PRR. Lastly, by using a compound exo1 mutant that was defective for interaction with Mlh1p and deficient for nuclease activity, we provide further evidence that Exo1p plays both structural and catalytic roles during MMR.

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Section: Discussionsupporting

confidence: 89%

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

et al. 2007

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“…We identified Elg1p-Rfc2-5p as a new suppressor of GCR in Saccharomyces cerevisiae through a genome wide screen in identifying additional GCR suppression pathways [13]. Independently, Elg1p-Rfc2-5p was discovered as a suppressor of the Ty1 mediated recombination and a synthetic lethality mutation with holiday junction resolvase mutations, mus81 or mms4 [10;11;12].…”

Section: Elg1 Functions In Dna Replication To Suppress Gcrmentioning

confidence: 99%

Suppression of gross chromosomal rearrangements by a new alternative replication factor C complex

Banerjee

Sikdar

Myung

2007

Biochemical and Biophysical Research Communications

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Defects in DNA replication fidelity lead to genomic instability. Gross chromosomal rearrangement (GCR), a type of genomic instability, is highly enhanced by various initial mutations affecting DNA replication. Frequent observations of GCRs in many cancers strongly argue the importance to maintain high fidelity of DNA replication to suppress carcinogenesis. Recent genome wide screens in Saccharomyces cerevisiae identified a new GCR suppressor gene, ELG1, enhanced level of genome instability gene 1. Its physical interaction with proliferating cell nuclear antigen (PCNA) and complex formation with Rfc2-5p proteins suggest that Elg1 functions to load/unload PCNA onto DNA during a certain DNA metabolism. High level of DNA damage accumulation and enhanced phenotypes with mutations in genes involved in cell cycle checkpoints, homologous recombination (HR), or chromatin assembly in the elg1 strain suggest that Elg1p-Rfc2-5p functions in a fundamental DNA metabolism to suppress genomic instability. KeywordsGenomic instability; DNA replication; ELG1; RFC; PCNA DNA is constantly challenged by intracellular as well as environmental stress. Inaccurate repair of DNA damage by such stress can result in genomic instability that can manifest as gross chromosomal rearrangements (GCRs). GCRs include translocations, deletions, inversions, amplifications, chromosome end-to-end fusions, and aneuploidy [1]. These genetic malformations often lead to cell death or carcinogenesis. Frequent observations of genomic instability in tumor cells support the argument for the importance of proper DNA repair to suppress carcinogenesis.Multiple mutations in cancer normally exceed the expected number of mutations that cells are able to obtain with normal mutation rates. In order to generate multiple mutations, cells must develop specific initial mutations that can facilitate further mutagenesis [2]. These initial mutations, known as mutator mutations, have been suggested to facilitate multiple mutations in many oncogenes and tumor suppressor genes during carcinogenesis. Mutator mutations were first proposed from cases of the hereditary nonpolyposis colorectal cancer Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access A new member of RFC family (ELG1-RFC)Processing of stalled replication forks are usually modulated by a homo-trimeric DNA sliding clamp called PCNA in eukaryotes. Differential post-translational modifications in PCNA have been documented as a regulatory mechanism for many different DNA metabolisms including GCR [5]. Replication factor C (RFC) complex is a heteropentameric ...

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“…Methods for the construction and propagation of gene-disrupted strains were described previously [10,14]. The sequences of primers used to generate gene-knockout cassettes and to confirm correct disruption are available upon request.…”

Section: General Genetic Methodsmentioning

confidence: 99%

“…The average GCR rates from at least two or more independent experiments using either 5 or 11 cultures for each strain are reported as previously described [10,14]. The sequences of breakpoints from mutants carrying GCR were determined as described [10,14].…”

Section: Characterization Of Spontaneous Gcr Rates and Chromosomal Brmentioning

confidence: 99%

“…Several studies using this approach have demonstrated that there are eight pathways for suppressing these chromosomal aberrations, while six pathways promote GCR formation. The suppression mechanisms include cell cycle checkpoints [7][8][9][10][11][12], post-replication [13,14] and mismatch repair [15,16], recombination pathways, an anti-de novo telomere addition mechanism [17,18], chromatin assembly factors [11,19], mechanisms that prevent end-to-end chromosome fusions [17,18,20] and a pathway detoxifying reactive oxygen species [14,21,22]. In contrast, the promoters of GCRs include telomerase-related factors [17,23], a mitotic checkpoint network [24], the Rad1-Rad10 endonuclease [25], non-homologous end-joining proteins including Lig4 and Nej1 [17], a pathway generating inappropriate recombination via sumoylation and the Srs2 helicase [13] and the Bre1 ubiquitin ligase [13].…”

Section: Introductionmentioning

confidence: 99%

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Smc5–Smc6 complex suppresses gross chromosomal rearrangements mediated by break-induced replications

et al. 2008

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Translocations in chromosomes alter genetic information. Although the frequent translocations observed in many tumors suggest the altered genetic information by translocation could promote tumorigenesis, the mechanisms for how translocations are suppressed and produced are poorly understood. The smc6-9 mutation increased the translocation class gross chromosomal rearrangement (GCR). Translocations produced in the smc6-9 strain are unique because they are nonreciprocal and dependent on break-induced replication (BIR) and independent of non-homologous end joining. The high incidence of translocations near repetitive sequences such as δ sequences, ARS, tRNA genes, and telomeres in the smc6-9 strain indicates that Smc5-Smc6 suppresses translocations by reducing DNA damage at repetitive sequences. Synergistic enhancements of translocations in strains defective in DNA damage checkpoints by the smc6-9 mutation without affecting de novo telomere addition class GCR suggest that Smc5-Smc6 defines a new pathway to suppress GCR formation.

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Mutator genes for suppression of gross chromosomal rearrangements identified by a genome-wide screening in Saccharomyces cerevisiae

Cited by 135 publications

References 51 publications

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

Suppression of gross chromosomal rearrangements by a new alternative replication factor C complex

Smc5–Smc6 complex suppresses gross chromosomal rearrangements mediated by break-induced replications

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