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  • 1
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    Leveraging DNA Damage Response Signaling to Identify Yeast Genes Controlling Genome Stability (2015)
    Genetics Society of America (GSA)
    Details
    Publication Date: 2015-05-12
    Description: Oncogenesis frequently is accompanied by rampant genome instability, which fuels genetic heterogeneity and resistance to targeted cancer therapy. We have developed an approach that allows precise, quantitative measurement of genome instability in high-throughput format in the Saccharomyces cerevisiae model system. Our approach takes advantage of the strongly DNA damage-inducible gene RNR3 , in conjunction with the reporter synthetic genetic array methodology, to infer mutants exhibiting genome instability by assaying for increased Rnr3 abundance. We screen for genome instability across a set of ~1000 essential and ~4200 nonessential mutant yeast alleles in untreated conditions and in the presence of the DNA-damaging agent methylmethane sulfonate. Our results provide broad insights into the cellular processes and pathways required for genome maintenance. Through comparison with existing genome instability screens, we isolated 130 genes that had not previously been linked to genome maintenance, 51% of which have human homologs. Several of these homologs are associated with a genome instability phenotype in human cells or are causally mutated in cancer. A comprehensive understanding of the processes required to prevent genome instability will facilitate a better understanding of its sources in oncogenesis.
    Electronic ISSN: 2160-1836
    Topics: Biology
    Published by Genetics Society of America (GSA)
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  • 2
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    Slx4 and Rtt107 control checkpoint signalling and DNA resection at double-strand breaks (2016)
    Oxford University Press
    Details
    Publication Date: 2016-01-30
    Description: The DNA damage checkpoint pathway is activated in response to DNA lesions and replication stress to preserve genome integrity. However, hyper-activation of this surveillance system is detrimental to the cell, because it might prevent cell cycle re-start after repair, which may also lead to senescence. Here we show that the scaffold proteins Slx4 and Rtt107 limit checkpoint signalling at a persistent double-strand DNA break (DSB) and at uncapped telomeres. We found that Slx4 is recruited within a few kilobases of an irreparable DSB, through the interaction with Rtt107 and the multi-BRCT domain scaffold Dpb11. In the absence of Slx4 or Rtt107, Rad9 binding near the irreparable DSB is increased, leading to robust checkpoint signalling and slower nucleolytic degradation of the 5' strand. Importantly, in slx4 sae2 double mutant cells these phenotypes are exacerbated, causing a severe Rad9-dependent defect in DSB repair. Our study sheds new light on the molecular mechanism that coordinates the processing and repair of DSBs with DNA damage checkpoint signalling, preserving genome integrity.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Genome-Scale Genetic Interactions and Cell Imaging Confirm Cytokinesis as Deleterious to Transient Topoisomerase II Deficiency in Saccharomyces cerevisiae (2017)
    Genetics Society of America (GSA)
    Details
    Publication Date: 2017-10-06
    Description: Topoisomerase II ( Top2 ) is an essential protein that resolves DNA catenations. When Top2 is inactivated, mitotic catastrophe results from massive entanglement of chromosomes. Top2 is also the target of many first-line anticancer drugs, the so-called Top2 poisons. Often, tumors become resistant to these drugs by acquiring hypomorphic mutations in the genes encoding Top2 . Here, we have compared the cell cycle and nuclear segregation of two coisogenic Saccharomyces cerevisiae strains carrying top2 thermosensitive alleles that differ in their resistance to Top2 poisons: the broadly-used poison-sensitive top2 -4 and the poison-resistant top2 -5 . Furthermore, we have performed genome-scale synthetic genetic array (SGA) analyses for both alleles under permissive conditions, chronic sublethal Top2 downregulation, and acute, yet transient, Top2 inactivation. We find that slowing down mitotic progression, especially at the time of execution of the mitotic exit network (MEN), protects against Top2 deficiency. In all conditions, genetic protection was stronger in top2 -5 ; this correlated with cell biology experiments in this mutant, whereby we observed destabilization of both chromatin and ultrafine anaphase bridges by execution of MEN and cytokinesis. Interestingly, whereas transient inactivation of the critical MEN driver Cdc15 partly suppressed top2 -5 lethality, this was not the case when earlier steps within anaphase were disrupted; i.e. , top2 -5 cdc14 -1 . We discuss the basis of this difference and suggest that accelerated progression through mitosis may be a therapeutic strategy to hypersensitize cancer cells carrying hypomorphic mutations in TOP2 .
    Electronic ISSN: 2160-1836
    Topics: Biology
    Published by Genetics Society of America (GSA)
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  • 4
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    Systematic analysis of complex genetic interactions (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018-04-20
    Description: To systematically explore complex genetic interactions, we constructed ~200,000 yeast triple mutants and scored negative trigenic interactions. We selected double-mutant query genes across a broad spectrum of biological processes, spanning a range of quantitative features of the global digenic interaction network and tested for a genetic interaction with a third mutation. Trigenic interactions often occurred among functionally related genes, and essential genes were hubs on the trigenic network. Despite their functional enrichment, trigenic interactions tended to link genes in distant bioprocesses and displayed a weaker magnitude than digenic interactions. We estimate that the global trigenic interaction network is ~100 times as large as the global digenic network, highlighting the potential for complex genetic interactions to affect the biology of inheritance, including the genotype-to-phenotype relationship.
    Keywords: Genetics, Online Only
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    Intersection of calorie restriction and magnesium in the suppression of genome-destabilizing RNA-DNA hybrids (2016)
    Oxford University Press
    Details
    Publication Date: 2016-10-14
    Description: Dietary calorie restriction is a broadly acting intervention that extends the lifespan of various organisms from yeast to mammals. On another front, magnesium (Mg 2+ ) is an essential biological metal critical to fundamental cellular processes and is commonly used as both a dietary supplement and treatment for some clinical conditions. If connections exist between calorie restriction and Mg 2+ is unknown. Here, we show that Mg 2+ , acting alone or in response to dietary calorie restriction, allows eukaryotic cells to combat genome-destabilizing and lifespan-shortening accumulations of RNA–DNA hybrids, or R-loops. In an R-loop accumulation model of Pbp1-deficient Saccharomyces cerevisiae , magnesium ions guided by cell membrane Mg 2+ transporters Alr1/2 act via Mg 2+ -sensitive R-loop suppressors Rnh1/201 and Pif1 to restore R-loop suppression, ribosomal DNA stability and cellular lifespan. Similarly, human cells deficient in ATXN2, the human ortholog of Pbp1, exhibit nuclear R-loop accumulations repressible by Mg 2+ in a process that is dependent on the TRPM7 Mg 2+ transporter and the RNaseH1 R-loop suppressor. Thus, we identify Mg 2+ as a biochemical signal of beneficial calorie restriction, reveal an R-loop suppressing function for human ATXN2 and propose that practical magnesium supplementation regimens can be used to combat R-loop accumulation linked to the dysfunction of disease-linked human genes.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Genetic Regulation of Dna2 Localization During the DNA Damage Response (2015)
    Genetics Society of America (GSA)
    Details
    Publication Date: 2015-09-02
    Description: DNA damage response pathways are crucial for protecting genome stability in all eukaryotes. Saccharomyces cerevisiae Dna2 has both helicase and nuclease activities that are essential for Okazaki fragment maturation, and Dna2 is involved in long-range DNA end resection at double-strand breaks. Dna2 forms nuclear foci in response to DNA replication stress and to double-strand breaks. We find that Dna2-GFP focus formation occurs mainly during S phase in unperturbed cells. Dna2 colocalizes in nuclear foci with 25 DNA repair proteins that define recombination repair centers in response to phleomycin-induced DNA damage. To systematically identify genes that affect Dna2 focus formation, we crossed Dna2-GFP into 4293 nonessential gene deletion mutants and assessed Dna2-GFP nuclear focus formation after phleomycin treatment. We identified 37 gene deletions that affect Dna2-GFP focus formation, 12 with fewer foci and 25 with increased foci. Together these data comprise a useful resource for understanding Dna2 regulation in response to DNA damage.
    Electronic ISSN: 2160-1836
    Topics: Biology
    Published by Genetics Society of America (GSA)
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