Mutability and mutational spectrum of chromosome transmission fidelity genes

Stirling, Peter C.; Crisp, Matthew J.; Basrai, Munira A.; Tucker, Cheryl M.; Dunham, Maitreya J.; Spencer, Forrest; Hieter, Philip

doi:10.1007/s00412-011-0356-3

Cited by 17 publications

(20 citation statements)

References 78 publications

(115 reference statements)

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“…The majority of these genes belong to biological processes, such as DNA repair, previously known to impact mutation rate, and ∼30% of the dMutator genes also cause chromosome instability as seen previously for LOF and ROF mutations (Stirling et al 2012). Incorporating the data from our screen with published data, a total of 210 genes are implicated in increasing the mutator phenotype in yeast (Huang et al 2003; Stirling et al 2012). …”

Section: Discussionmentioning

confidence: 71%

“…The budding yeast Saccharomyces cerevisiae has been a valuable model system for delineating pathways involved in genome instability, and screens in yeast have identified mutator alleles that increase genome instability (Huang et al 2003; Yuen et al 2007; Stirling et al 2012). A forward mutation screen with the nonessential yeast deletion collection identified 33 genes whose null mutations resulted in a mutator phenotype (Huang et al 2003), and 38 essential genes were identified in another screen (Stirling et al 2014).…”

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confidence: 99%

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Dosage Mutator Genes in Saccharomyces cerevisiae: A Novel Mutator Mode-of-Action of the Mph1 DNA Helicase

et al. 2016

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Mutations that cause genome instability are considered important predisposing events that contribute to initiation and progression of cancer. Genome instability arises either due to defects in genes that cause an increased mutation rate (mutator phenotype), or defects in genes that cause chromosome instability (CIN). To extend the catalog of genome instability genes, we systematically explored the effects of gene overexpression on mutation rate, using a forward-mutation screen in budding yeast. We screened ∼5100 plasmids, each overexpressing a unique single gene, and characterized the five strongest mutators, MPH1 (mutator phenotype 1), RRM3, UBP12, PIF1, and DNA2. We show that, for MPH1, the yeast homolog of Fanconi Anemia complementation group M (FANCM), the overexpression mutator phenotype is distinct from that of mph1Δ. Moreover, while four of our top hits encode DNA helicases, the overexpression of 48 other DNA helicases did not cause a mutator phenotype, suggesting this is not a general property of helicases. For Mph1 overexpression, helicase activity was not required for the mutator phenotype; in contrast Mph1 DEAH-box function was required for hypermutation. Mutagenesis by MPH1 overexpression was independent of translesion synthesis (TLS), but was suppressed by overexpression of RAD27, a conserved flap endonuclease. We propose that binding of DNA flap structures by excess Mph1 may block Rad27 action, creating a mutator phenotype that phenocopies rad27Δ. We believe this represents a novel mutator mode-of-action and opens up new prospects to understand how upregulation of DNA repair proteins may contribute to mutagenesis.

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Section: Discussionmentioning

confidence: 71%

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confidence: 99%

Dosage Mutator Genes in Saccharomyces cerevisiae: A Novel Mutator Mode-of-Action of the Mph1 DNA Helicase

et al. 2016

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“…We found that clb5 Δ clb6 Δ most strongly correlated with mutations affecting the establishment of sister-chromatid cohesion, including point mutants in cohesin, smc1-259 , smc3-1 , smc3-42 and in the cohesin loading factor Scc2 ( scc2-4 ) as well as with deletions in CTF4 and CTF18, (Stirling et al, 2012; Yuen et al, 2007) (Figure 6C; Supp. Data 8).…”

Section: Resultsmentioning

confidence: 89%

Systematic Triple-Mutant Analysis Uncovers Functional Connectivity between Pathways Involved in Chromosome Regulation

Haber¹,

Braberg²,

Wu³

et al. 2013

Cell Reports

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Genetic interactions reveal the functional relationships between pairs of genes. In this study, we describe a method for the systematic generation and quantitation of triple mutants, termed Triple Mutant Analysis (TMA). We have used this approach to interrogate partially redundant pairs of genes in S. cerevisiae, including ASF1 and CAC1, two histone chaperones. After subjecting asf1Δ cac1Δ to TMA, we found that the Swi/Snf Rdh54 protein, compensates for the absence of Asf1 and Cac1. Rdh54 more strongly associates with the chromatin apparatus and the pericentromeric region in the double mutant. Moreover, Asf1 is responsible for the synthetic lethality observed in cac1Δ strains lacking the HIRA-like proteins. A similar TMA was carried out after deleting both CLB5 and CLB6, cyclins that regulate DNA replication, revealing a strong functional connection to chromosome segregation. This approach can reveal functional redundancies that cannot be uncovered using traditional double mutant analyses.

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“…For these reasons, defining genes and pathways that drive CIN and understanding the mechanisms that underlie genome stability will contribute not only to an understanding of tumor etiology and progression but will also be relevant for guiding therapeutic strategies. The budding yeast Saccharomyces cerevisiae has served as an excellent model system for studying highly conserved biological pathways and has been instrumental in delineating pathways involved in genome instability (9). Although the complete spectrum of genes that are mutable to a CIN phenotype [loss-of-function (LOF) and reductionof-function (ROF) alleles] have been determined in yeast (10,11), the spectrum of genes that when amplified or overexpressed cause CIN are less well-defined (12,13).…”

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confidence: 99%

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Duffy

Fam

Wang

et al. 2016

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

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Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.dosage chromosome instability | overexpression | synthetic dosage lethality | TDP1 | rhabdomyosarcoma

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Mutability and mutational spectrum of chromosome transmission fidelity genes

Cited by 17 publications

References 78 publications

Dosage Mutator Genes in Saccharomyces cerevisiae: A Novel Mutator Mode-of-Action of the Mph1 DNA Helicase

Dosage Mutator Genes in Saccharomyces cerevisiae: A Novel Mutator Mode-of-Action of the Mph1 DNA Helicase

Systematic Triple-Mutant Analysis Uncovers Functional Connectivity between Pathways Involved in Chromosome Regulation

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

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