The RecQ4 Orthologue Hrq1 Is Critical for DNA Interstrand Cross-Link Repair and Genome Stability in Fission Yeast

Groocock, Lynda M.; Prudden, John; Perry, J. Jefferson P.; Boddy, Michael N.

doi:10.1128/mcb.06184-11

Cited by 35 publications

(38 citation statements)

References 65 publications

(80 reference statements)

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“…Similar to our findings in S. cerevisiae, in Schizosaccharomyces pombe, hrq1 mutations are epistatic to NER and synergistic to PRR with respect to cisplatin (37). However, our model differs from the S. pombe one, which has HR acting downstream of PRR.…”

Section: Clik Analysis Captures Additional Biologicallysupporting

confidence: 82%

Physical and genetic-interaction density reveals functional organization and informs significance cutoffs in genome-wide screens

Dittmar

Pierce

Rothstein

et al. 2013

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

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Genome-wide experiments often measure quantitative differences between treated and untreated cells to identify affected strains. For these studies, statistical models are typically used to determine significance cutoffs. We developed a method termed "CLIK" (Cutoff Linked to Interaction Knowledge) that overlays biological knowledge from the interactome on screen results to derive a cutoff. The method takes advantage of the fact that groups of functionally related interacting genes often respond similarly to experimental conditions and, thus, cluster in a ranked list of screen results. We applied CLIK analysis to five screens of the yeast gene disruption library and found that it defined a significance cutoff that differed from traditional statistics. Importantly, verification experiments revealed that the CLIK cutoff correlated with the position in the rank order where the rate of true positives drops off significantly. In addition, the gene sets defined by CLIK analysis often provide further biological perspectives. For example, applying CLIK analysis retrospectively to a screen for cisplatin sensitivity allowed us to identify the importance of the Hrq1 helicase in DNA crosslink repair. Furthermore, we demonstrate the utility of CLIK to determine optimal treatment conditions by analyzing genome-wide screens at multiple rapamycin concentrations. We show that CLIK is an extremely useful tool for evaluating screen quality, determining screen cutoffs, and comparing results between screens. Furthermore, because CLIK uses previously annotated interaction data to determine biologically informed cutoffs, it provides additional insights into screen results, which supplement traditional statistical approaches.bioinformatics | false discovery rate

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Section: Clik Analysis Captures Additional Biologicallysupporting

confidence: 82%

Physical and genetic-interaction density reveals functional organization and informs significance cutoffs in genome-wide screens

Dittmar

Pierce

Rothstein

et al. 2013

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

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“…Although our study is the first report of MMC or 8-MOP sensitivity for hrq1 S. cerevisiae , S. pombe hrq1 Δ cells are highly sensitive to both cisplatin and MMC (Groocock et al, 2012). However, because 8-MOP was not tested in that study, it is possible that the S. pombe hrq1 Δ MMC sensitivity is due to the low level of intra-strand crosslinks generated by MMC.…”

Section: Discussionmentioning

confidence: 75%

Hrq1, a Homolog of the Human RecQ4 Helicase, Acts Catalytically and Structurally to Promote Genome Integrity

Bochman¹,

Paeschke²,

Chan³

et al. 2014

Cell Reports

133

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Summary Human RecQ4 affects cancer and aging, but it is difficult to study because it is a fusion between a helicase and an essential replication factor. Budding yeast Hrq1 is homologous to the disease-linked helicase domain of RecQ4 and, like hRecQ4, was a robust 3’–5’ helicase. Additionally, Hrq1 had the unusual property of forming heptameric rings. Cells lacking Hrq1 exhibited two particularly dangerous DNA damage phenotypes: hypersensitivity to DNA inter-strand crosslinks (ICLs) and telomere addition to DNA breaks. Both activities are rare: their co-existing in a single protein is unprecedented. Resistance to ICLs required helicase activity, but suppression of telomere addition did not. Hrq1 also affected telomere length by a non-catalytic mechanism, as well as telomerase-independent telomere maintenance. As Hrq1 bound telomeres in vivo, it likely affects them directly. Thus, the tumor suppressing activity of RecQ4 could be due to a role in ICL repair and/or suppressing de novo telomere addition.

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“…Table S2). RecQ AN10757 is a homolog of yeast Hrq1, which is reported to support the repair of excised nucleotides (62). The putative DNA helicase AN5278 and DNA repair nuclease AN3118 were only detected in sector (supplemental Table S2) and are the homologs of yeast Pif1 (26%) and Mus81 (36% identity), respectively.…”

Section: Up-regulated Transporters To Elevate Mitochondrial Camentioning

confidence: 99%

Linkage of Oxidative Stress and Mitochondrial Dysfunctions to Spontaneous Culture Degeneration in Aspergillus nidulans

Lin

Xia

et al. 2014

Molecular & Cellular Proteomics

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Filamentous fungi including mushrooms frequently and spontaneously degenerate during subsequent culture maintenance on artificial media, which shows the loss or reduction abilities of asexual sporulation, sexuality, fruiting, and production of secondary metabolites, thus leading to economic losses during mass production. To better understand the underlying mechanisms of fungal degeneration, the model fungus Aspergillus nidulans was employed in this study for comprehensive analyses. First, linkage of oxidative stress to culture degeneration was evident in A. nidulans. Taken together with the verifications of cell biology and biochemical data, a comparative mitochondrial proteome analysis revealed that, unlike the healthy wild type, a spontaneous fluffy sector culture of A. nidulans demonstrated the characteristics of mitochondrial dysfunctions. Relative to the wild type, the features of cytochrome c release, calcium overload and up-regulation of apoptosis inducing factors evident in sector mitochondria suggested a linkage of fungal degeneration to cell apoptosis. However, the sector culture could still be maintained for generations without the signs of growth arrest. Up-regulation of the heat shock protein chaperones, anti-apoptotic factors and DNA repair proteins in the sector could account for the compromise in cell death. The results of this study not only shed new lights on the mechanisms of spontaneous degeneration of fungal cultures but will also provide alternative biomarkers to monitor fungal culture degeneration. Molecular & Cellular Proteomics

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The RecQ4 Orthologue Hrq1 Is Critical for DNA Interstrand Cross-Link Repair and Genome Stability in Fission Yeast

Cited by 35 publications

References 65 publications

Physical and genetic-interaction density reveals functional organization and informs significance cutoffs in genome-wide screens

Physical and genetic-interaction density reveals functional organization and informs significance cutoffs in genome-wide screens

Hrq1, a Homolog of the Human RecQ4 Helicase, Acts Catalytically and Structurally to Promote Genome Integrity

Linkage of Oxidative Stress and Mitochondrial Dysfunctions to Spontaneous Culture Degeneration in Aspergillus nidulans

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