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Cited by 16Fungal and yeast genetics researchAntifungal resistance and susceptibilityGenomics and Chromatin Dynamics

SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes

Open access
Nikolov, Vladislav N., Malavia, Dhara, Kubota, Takashi·2022·Nature Communications
DOI 10.1038/s41467-022-29591-zPMC PMC9005695
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Abstract

The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae , Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata , Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance.

AI snapshot

Written from the paper’s full text.

TL;DR

Rtt106 and SWI/SNF are chromatin regulators that drive expression of the fungal Pleiotropic Drug Resistance (PDR) network and confer azole antifungal resistance. In *S. cerevisiae*, Rtt106 acts through Pdr3 for basal PDR gene expression, while SWI/SNF supports both basal and drug-induced expression; related roles are conserved in *C. glabrata*.

Key findings

  • Rtt106 binds PDR network gene promoters, including *PDR5*, at PDRE sites; 19 of 20 promoters in cluster 1 belong to PDR network genes, and Rtt106 binding there depends on Pdr3 but not Pdr1.
  • Loss of Rtt106 reduced mRNA levels of 16 of 20 Type A PDR network genes, with strong reductions in *PDR5*, *CIS1*, and *RSB1*; *pdr3Δ* showed similar reductions, while *pdr1Δ* did not.
  • Pdr1, but neither Pdr3 nor Rtt106, was required for ketoconazole-induced transient expression of 22 PDR network genes increased more than 4-fold in WT.
  • SWI/SNF was required for both basal and ketoconazole-induced PDR gene expression; *snf2Δ* reduced *PDR5* mRNA and was highly azole-sensitive. In *C. glabrata*, loss of CgRtt106 or CgSnf2 reduced ketoconazole-induced *CgCDR1*/*CgCDR2* expression and increased azole sensitivity.

Methods

  • Used *S. cerevisiae* (S288C/BY4741 backgrounds) and *C. glabrata* (ATCC 2001), with ChIP-seq, ChIP-qPCR, RNA-seq, Northern blot, luciferase reporter, western blot, GST pull-down, spot assays, and SILAC-based minichromosome proteomics.
  • ChIP-seq classified Rtt106 promoter binding into clusters/types based on WT binding and changes in *pdr1Δ pdr3Δ*, *hir1Δ*, and *yta7Δ*; RNA-seq differential expression used edgeR with FDR < 0.05, and GO analysis used GO Term Finder.
  • Nucleosome and TBP analyses reused published MNase-seq, ChEC-seq, and TSS datasets; most ChIP-qPCR/RNA-seq experiments used three biological replicates, while minichromosome mass spectrometry was performed once.

Limitations

  • The paper states that it remains unknown whether Rtt106-regulated basal *PDR5* expression directly leads to drug resistance, and whether Rtt106 affects drug-induced *PDR5* expression during long-term drug exposure.
  • The authors could not test mitochondrial dysfunction-mediated drug resistance because the phenotype was not reproducibly observed in their strain background; how Rtt106 binds Pdr3 and how CgRtt106/CgSWI/SNF upregulate drug-induced expression also remain to be elucidated.
  • Evident from the text: minichromosome mass spectrometry was n = 1, some validation experiments were n = 1 or representative repeats, and the study does not test clinical *C. glabrata* isolates or directly assay nucleosome turnover at *PDR5*.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41467-022-29591-z

Cites

73 of 73 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 96 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    No obvious correlation of genes whose expression increased in rtt106Δ and Rtt106 binding at those genes was observed.

    “No obvious correlation of genes whose expression increased in rtt106Δ and Rtt106 binding at those genes was observed.”
    Quote in the paperNot a substantial claim
  • Findingown data

    All three types of Rtt106-bound promoters show atypically wide NDRs.

    “We observed that all three types of Rtt106-bound promoters show atypically wide NDRs (Fig. 2g)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Rtt106 peak summits coincide with the PDRE in promoters such as PDR5, PDR15, SNQ2 and SPO24.

    “Furthermore, the Rtt106 peak summits coincided with the PDRE in such promoters e.g. PDR5, PDR15, SNQ2 and SPO24 (Fig. 2a, Rtt106 ChIP in WT).”
    Quote in the paperSubstantial claim
  • Findingown data

    Rtt106 binding to the PDRE-containing promoters is almost completely abolished in the absence of both Pdr1 and Pdr3.

    “Rtt106 binding to the PDRE-containing promoters was almost completely abolished in the absence of both Pdr1 and Pdr3 (Fig. 2a, Rtt106 ChIP in pdr1Δ pdr3Δ)”
    Quote in the paperSubstantial claim
  • Findingown data

    No common feature was found in the Type C promoter regions.

    “No common feature was found in these promoter regions.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 53
  • May combine two claims. 64

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Rtt106 localises at the promoter of the histone gene pair HTA1-HTB1 in S. cerevisiae.

    “As expected31,32, Rtt106 localised at the promoter of the histone gene pair HTA1-HTB1 (Fig. 1a).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Fillingham, J. et al. Two-color cell array screen reveals interdependent roles for histone chaperones and a chromatin boundary regulator in histone gene repression. Mol. Cell 35, 340–351 (2009). source

      Not checked in the free run.

    • cites [32] Zunder, R. M. & Rine, J. Direct interplay among histones, histone chaperones, and a chromatin boundary protein in the control of histone gene expression. Mol. Cell Biol. 32, 4337–4349 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Type C promoters contain some non-PDR transporter genes (FUI1, CTR1, FTR1, PMA1, PHO87 and PUT4) but do not include any PDR genes.

    “This third type contains some non-PDR transporter genes, e.g. FUI1, CTR1, FTR1, PMA1, PHO87 and PUT4, but does not include any PDR genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In our experiments, only HHF1 mRNA was significantly increased in rtt106Δ, unlike previous reports which found additional histone genes affected.

    “Regarding histone gene expression, in our experiments only HHF1 mRNA was significantly increased in rtt106Δ (Fig. 3a and Supplementary Data 3), unlike previous reports which found additional histone genes affected31,32.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Fillingham, J. et al. Two-color cell array screen reveals interdependent roles for histone chaperones and a chromatin boundary regulator in histone gene repression. Mol. Cell 35, 340–351 (2009). source

      Not checked in the free run.

    • cites [32] Zunder, R. M. & Rine, J. Direct interplay among histones, histone chaperones, and a chromatin boundary protein in the control of histone gene expression. Mol. Cell Biol. 32, 4337–4349 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Loss of Rtt106 causes a significant reduction of mRNA levels of the majority of the PDR network genes whose promoters it binds (16 out of 20 genes in Type A), with a particular reduction in PDR5, CIS1 and RSB1 expression.

    “Loss of Rtt106 caused a significant reduction of mRNA levels of the majority of the PDR network genes whose promoters it binds (16 out of 20 genes in Type A), with a particular reduction in PDR5, CIS1 and RSB1 expression (Fig. 3a and Supplementary Fig. 2a and Supplementary Data 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The yta7Δ mutation does not cause Rtt106 binding to spread from PDRE-containing promoters, unlike at the histone promoters where Rtt106 spreads into regions normally occupied by Yta7.

    “However, the yta7Δ mutation did not cause Rtt106 binding to spread from PDRE-containing promoters, unlike at the histone promoters where Rtt106 was observed to spread into regions normally occupied by Yta7 (Fig. 2a, b, compare our Rtt106 ChIP data with the published Yta7 ChIP data shown at bottom29).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Lombardi, L. M., Davis, M. D. & Rine, J. Maintenance of nucleosomal balance in cis by conserved AAA-ATPase Yta7. Genetics 199, 105–116 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In clusters 7 and 8, Rtt106 shows clear peaks that do not depend on Pdr1, Pdr3 or HIR, and are not limited by loss of Yta7.

    “In clusters 7 and 8, we found another type of Rtt106-binding promoters, where Rtt106 shows clear peaks (rather than broader signals) that do not depend on Pdr1, Pdr3 or HIR, and are not limited by the loss of Yta7 (Fig. 2e, ‘peaks’ in clusters 7 and 8, and Supplementary Fig. 1b and Supplementary Data 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Rtt106 is also enriched at centromeres, tRNA, snoRNA, and gene bodies of highly expressed genes, mainly found in clusters 7-9.

    “Rtt106 was also enriched at centromeres, tRNA, snoRNA, and gene bodies of highly expressed genes, mainly found in clusters 7–9 (Fig. 2e and Supplementary Fig. 1d and Supplementary Data 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Almost all PDR network genes whose mRNA levels were reduced in rtt106Δ showed a similar reduction in pdr3Δ; however, no reduction was observed in the mRNA for most such genes in pdr1Δ.

    “Almost all PDR network genes whose mRNA levels were reduced in rtt106Δ showed a similar reduction in pdr3Δ; however, no reduction was observed in the mRNA for most such genes in pdr1Δ (Fig. 3c, d and Supplementary Data 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Gene ontology analysis of downregulated genes in rtt106Δ shows significant enrichment of 'Transmembrane transport' genes, and 8 out of the 20 most reduced mRNAs correspond to transporter genes.

    “Gene ontology analysis of the downregulated genes in rtt106Δ show significant enrichment of ‘Transmembrane transport’ genes (Fig. 3b), and 8 out of the 20 most reduced mRNA in rtt106Δ correspond to transporter genes (Supplementary Fig. 2a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cluster 2 includes all histone gene pairs except HTA2-HTB2, as well as AGP1 and ECL1.

    “This cluster included all histone gene pairs (except HTA2-HTB2 where Rtt106 does not bind strongly), as well as AGP1 and ECL1 (Fig. 2b, e, f)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither pdr1Δ nor pdr3Δ mutations caused increased mRNA from genes with low expression levels.

    “As expected, neither pdr1Δ nor pdr3Δ mutations caused increased mRNA from genes with low expression levels (‘+’ symbols in Fig. 3c, d), consistent with the effect on these genes in rtt106Δ being due to a general histone occupancy defect, occurring independently of Pdr3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cluster 2 contains promoters bound by Rtt106 dependent on HIR and limited by Yta7, but not dependent on Pdr1/3.

    “Cluster 2 contains promoters bound by Rtt106 dependent on HIR and limited by Yta7, but not dependent on Pdr1/3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both Pdr1 and Pdr3 bind purified SWI/SNF in GST pull-down analyses.

    “Furthermore, GST pull-down analyses showed that both Pdr1 and Pdr3 bind purified SWI/SNF (Fig. 5f, g and Supplementary Fig. 6b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The SWI/SNF ATP-dependent chromatin-remodelling complex and the transcriptional regulatory protein Ume6 are enriched on the PDR5 promoter.

    “Interestingly, we identified the SWI/SNF ATP-dependent chromatin-remodelling complex and the transcriptional regulatory protein Ume6 (Fig. 5b and Supplementary Data 5) as enriched on the PDR5 promoter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rtt106 is enriched on the PDR5 promoter by western blot, although it was not identified by mass spectrometry.

    “Rtt106 enrichment on the PDR5 promoter was confirmed by western blot analysis, although it was not identified by mass spectrometry (Supplementary Fig. 6a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Deletion of PDR3 caused almost complete loss of Rtt106 recruitment to the PDR5 promoter, while deletion of PDR1 increased recruitment of Rtt106 to the PDR5 promoter.

    “Strikingly, deletion of PDR3 caused almost complete loss of Rtt106 recruitment to the PDR5 promoter, while deletion of PDR1 actually increased recruitment of Rtt106 to the PDR5 promoter (Fig. 4d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Loss of Rtt106 sensitises pdr3-GOF but not pdr1-GOF to ketoconazole.

    “Consistently, loss of Rtt106 sensitised pdr3-GOF, but not pdr1-GOF, to ketoconazole (Fig. 4h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PDR1 is essential for the ketoconazole-induced, transient expression of these 22 genes, but neither PDR3 nor RTT106 is required.

    “We found that PDR1 is essential for the ketoconazole-induced, transient expression of these 22 genes, but neither PDR3 nor RTT106 is required (Fig. 3f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rtt106 is not essential for Pdr3 recruitment to the PDR5 promoter; Pdr3 is still recruited there in the absence of Rtt106.

    “Conversely, Rtt106 is not essential for Pdr3 recruitment to the PDR5 promoter, as Pdr3 is still recruited there in the absence of Rtt106, as shown by ChIP-qPCR using a tagged PDR3-13Myc strain confirmed as retaining protein function (Supplementary Fig. 4a–d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    pdr3Δ and rtt106Δ are sensitive to high doses of ketoconazole, while pdr1Δ is sensitive only to low doses but not to high doses.

    “We further observed that pdr3Δ and rtt106Δ are sensitive to high doses of ketoconazole, while pdr1Δ is sensitive only to low doses but not to high doses (Supplementary Fig. 3f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SWI/SNF is essential for both basal and drug-induced expression of the PDR network genes.

    “while SWI/SNF is essential for both basal and drug-induced expression.”
    • Also stated in: § Introduction · boosted
      “We further show that SWI/SNF acts as an essential activator of the PDR network genes for both basal and azole-induced expression, and therefore is essential for drug resistance of wild-type S. cerevisiae, and of a pdr3-GOF mutant.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Northern blot analyses confirmed that Rtt106 acts with Pdr3 to mediate basal expression of PDR5, but Rtt106 is not essential for Pdr1-mediated transient expression of PDR5 in response to ketoconazole.

    “In addition to RNA-seq (Fig. 3), Northern blot analyses confirmed that Rtt106 acts with Pdr3 to mediate basal expression of PDR5, but Rtt106 is not essential for Pdr1-mediated transient expression of PDR5 in response to ketoconazole (Supplementary Fig. 3a–d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Loss of Rtt106 reduces PDR5 mRNA in a pdr3-GOF (pdr3-2) mutant but not in a pdr1-GOF (pdr1-3) mutant.

    “As expected, loss of Rtt106 caused the reduction of PDR5 mRNA in a pdr3-GOF (pdr3-2) mutant, but not in a pdr1-GOF (pdr1-3) mutant (Fig. 4g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rtt106 is required for activating the PDR5 promoter and for maintaining Pdr5 protein levels under non-drug-treated conditions.

    “We further found using a luciferase expression assay that Rtt106 is required for activating the PDR5 promoter (Fig. 4a), and therefore for maintaining Pdr5 protein levels under non-drug-treated conditions (western blot analysis; Fig. 4b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The minichromosome isolation/SILAC proteomics approach identified PDR5 promoter-binding proteins including Pdr1, Pdr3, and the RNA polymerase II Mediator complex, validating the approach.

    “We successfully identified PDR5 promoter-binding proteins including transcription factors Pdr1 and Pdr3, and the RNA polymerase II Mediator complex that binds Pdr1 and Pdr37,47, validating this approach for capturing promoter-binding proteins in a near-native context (Fig. 5b and Supplementary Data 5).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Thakur, J. K. et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452, 604–609 (2008). source

      Not checked in the free run.

    • cites [47] Shahi, P., Gulshan, K., Näär, A. M. & Moye-Rowley, W. S. Differential roles of transcriptional mediator subunits in regulation of multidrug resistance gene expression in Saccharomyces cerevisiae. Mol. Biol. Cell 21, 2469–2482 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Cgsnf2Δ and, to a lesser extent, Cgrtt106Δ exhibit increased sensitivity to ketoconazole and fluconazole, along with a hyper-sensitive Cgcdr1Δ.

    “We finally observed that along with a hyper-sensitive Cgcdr1Δ, Cgsnf2Δ and, to a lesser extent, Cgrtt106Δ exhibited increased sensitivity to ketoconazole and fluconazole (Fig. 7e).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Sequencing confirmed that pdr1-3 contains mutations Q411K, F815S, T820A, T921I and loss of 5Ns at 1011 aa, and pdr3-2 contains Q56R, H110Q, G834S, A885T, N916S and E941G.

    “Sequencing of the inserted pdr1-3 and pdr3-2 genes in the S288C backgrounds confirmed that pdr1-3 contains the following mutations compared to the S288C reference genome: Q411K, F815S, T820A, T921I and loss of 5Ns at 1011 aa, while pdr3-2 contains Q56R, H110Q, G834S, A885T, N916S and E941G.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CgRtt106 and CgSWI/SNF also localise at the CgCDR1 promoter in YPD.

    “CgRtt106 and CgSWI/SNF also localise at the CgCDR1 promoter in YPD (Supplementary Fig. 8c), with higher background binding of CgRtt106 to a control locus probably because of its function in DNA replication.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi.

    “The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance.”
    • Also stated in: § Introduction · plain
      “the Pleiotropic Drug Resistance (PDR) network of fungi works as the first line of defence against a broad range of xenobiotics4,5, and is central to the fungal drug response6,7.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] Sipos, G. & Kuchler, K. Fungal ATP-binding cassette (ABC) transporters in drug resistance & detoxification. Curr. Drug Targets 7, 471–481 (2006). source

      Not checked in the free run.

    • cites [5] Balzi, E. & Goffeau, A. Yeast multidrug resistance: the PDR network. J. Bioenerg. Biomembr. 27, 71–76 (1995). source

      Not checked in the free run.

    • cites [6] Paul, S. & Moye-Rowley, W. S. Multidrug resistance in fungi: regulation of transporter-encoding gene expression. Front. Physiol. 5, 143 (2014). source

      Not checked in the free run.

    • cites [7] Thakur, J. K. et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452, 604–609 (2008). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Pdr5, a major ATP-binding cassette (ABC) multidrug transporter, is critical for drug resistance in Saccharomyces cerevisiae.

    “Among the PDR network gene products, Pdr5, a major ATP-binding cassette (ABC) multidrug transporter, is critical for drug resistance in Saccharomyces cerevisiae8, a fungus closely related to the pathogenic fungus Candida glabrata.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Golin, J. & Ambudkar, S. V. The multidrug transporter Pdr5 on the 25th anniversary of its discovery: an important model for the study of asymmetric ABC transporters. Biochem. J. 467, 353–363 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Overactivation of the PDR network is associated with drug resistance.

    “The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Pdr5 overexpression is one of the main causes of drug resistance in S. cerevisiae.

    “Pdr5 overexpression is one of the main causes of drug resistance in S. cerevisiae8.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Golin, J. & Ambudkar, S. V. The multidrug transporter Pdr5 on the 25th anniversary of its discovery: an important model for the study of asymmetric ABC transporters. Biochem. J. 467, 353–363 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pdr1 activates increased gene expression in response to direct binding to the azole antifungal ketoconazole.

    “Pdr1 and Pdr3 together sustain basal gene expression, and Pdr1 activates increased gene expression in response to direct binding to the azole antifungal ketoconazole7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Thakur, J. K. et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452, 604–609 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The yeast SWI/SNF complex is an ATP-dependent chromatin-remodelling complex composed of 12 subunits, 5 of which are fungal-specific.

    “The yeast SWI/SNF complex is an ATP-dependent chromatin-remodelling complex, and it is composed of 12 subunits, 5 of which are fungal-specific36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Wang, C. et al. Structure of the yeast Swi/Snf complex in a nucleosome free state. Nat. Commun. 11, 3398 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Loss of Rtt106 causes aberrant 'cryptic' transcription initiation within gene bodies and compromised silencing at the mating loci and telomeres, likely due to defective nucleosome assembly.

    “Loss of Rtt106 causes aberrant ‘cryptic’ transcription initiation within gene bodies26 and compromised silencing at the mating loci and telomeres27,28, likely due to defective nucleosome assembly26,27,29.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [26] Imbeault, D., Gamar, L., Rufiange, A., Paquet, E. & Nourani, A. The Rtt106 histone chaperone is functionally linked to transcription elongation and is involved in the regulation of spurious transcription from cryptic promoters in yeast. J. Biol. Chem. 283, 27350–27354 (2008). source

      Not checked in the free run.

    • cites [27] Zunder, R. M., Antczak, A. J., Berger, J. M. & Rine, J. Two surfaces on the histone chaperone Rtt106 mediate histone binding, replication, and silencing. Proc. Natl Acad. Sci. USA 109, E144–E153 (2012). source

      Not checked in the free run.

    • cites [28] Huang, S. et al. Rtt106p is a histone chaperone involved in heterochromatin-mediated silencing. Proc. Natl Acad. Sci. USA 102, 13410–13415 (2005). source

      Not checked in the free run.

    • cites [29] Lombardi, L. M., Davis, M. D. & Rine, J. Maintenance of nucleosomal balance in cis by conserved AAA-ATPase Yta7. Genetics 199, 105–116 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the late G1 and early S phase, Rtt106 recruits SWI/SNF, which activates transcription of the histone genes by releasing HIR- and RSC-mediated repression.

    “In contrast, in the late G1 and early S phase Rtt106 recruits SWI/SNF, another ATP-dependent chromatin-remodelling complex, which activates transcription of the histone genes by releasing HIR- and RSC-mediated repression33,34.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Ferreira, M. E., Flaherty, K. & Prochasson, P. The Saccharomyces cerevisiae histone chaperone Rtt106 Mediates the cell cycle recruitment of SWI/SNF and RSC to the HIR-dependent histone genes. PLoS ONE 6, e21113 (2011). source

      Not checked in the free run.

    • cites [34] Dimova, D., Nackerdien, Z., Furgeson, S., Eguchi, S. & Osley, M. A. A role for transcriptional repressors in targeting the yeast Swi/Snf complex. Mol. Cell 4, 75–83 (1999). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recruitment of SWI/SNF to promoters can be mediated through sequence-specific transcription factors including Gcn4, Pho4, Swi5 and Hap4.

    “Recruitment of SWI/SNF to promoters can be mediated through sequence-specific transcription factors including Gcn4, Pho4, Swi5 and Hap441,42.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Yudkovsky, N., Logie, C., Hahn, S. & Peterson, C. L. Recruitment of the SWI/SNF chromatin remodeling complex by transcriptional activators. Genes Dev. 13, 2369–2374 (1999). source

      Not checked in the free run.

    • cites [42] Neely, K. E., Hassan, A. H., Brown, C. E., Howe, L. & Workman, J. L. Transcription activator interactions with multiple SWI/SNF subunits. Mol. Cell Biol. 22, 1615–1625 (2002). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pdr1 and Pdr3 together sustain basal gene expression.

    “Pdr1 and Pdr3 together sustain basal gene expression, and Pdr1 activates increased gene expression in response to direct binding to the azole antifungal ketoconazole7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Thakur, J. K. et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452, 604–609 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rtt106, a fungal-specific histone chaperone, functions in histone deposition during DNA replication and transcription elongation in S. cerevisiae, and preferentially binds H3K56-acetylated histone H3-H4.

    “Rtt106, a fungal-specific histone chaperone, functions in histone deposition during DNA replication and transcription elongation in S. cerevisiae, and preferentially binds H3K56-acetylated histone H3-H424–26.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Su, D. et al. Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106. Nature 483, 104–107 (2012). source

      Not checked in the free run.

    • cites [25] Li, Q. et al. Acetylation of histone H3 lysine 56 regulates replication-coupled nucleosome assembly. Cell 134, 244–255 (2008). source

      Not checked in the free run.

    • cites [26] Imbeault, D., Gamar, L., Rufiange, A., Paquet, E. & Nourani, A. The Rtt106 histone chaperone is functionally linked to transcription elongation and is involved in the regulation of spurious transcription from cryptic promoters in yeast. J. Biol. Chem. 283, 27350–27354 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hyperactivation of Pdr1 or Pdr3 can be caused by gain-of-function (GOF) mutations in PDR1 or PDR3.

    “Such hyperactivation can be caused by gain-of-function (GOF) mutations in PDR1 or PDR314,15 or mitochondrial dysfunction (e.g. loss of the mitochondrial genome), the latter of which only stimulates Pdr3-dependent gene expression16.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Meyers, S. et al. Interaction of the yeast pleiotropic drug resistance genes PDR1 and PDR5. Curr. Genet. 21, 431–436 (1992). source

      Not checked in the free run.

    • cites [15] Wolfger, H., Mahe, Y., Parle-McDermott, A., Delahodde, A. & Kuchler, K. The yeast ATP binding cassette (ABC) protein genes PDR10 and PDR15 are novel targets for the Pdr1 and Pdr3 transcriptional regulators. FEBS Lett. 418, 269–274 (1997). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Outside S phase, Rtt106 forms a repressive complex together with other histone chaperones HIR and Asf1 to recruit RSC to the histone promoters.

    “Outside S phase, Rtt106 forms a repressive complex together with other histone chaperones HIR and Asf1 to recruit RSC (Remodel the Structure of Chromatin), an essential ATP-dependent chromatin-remodelling complex, to the histone promoters31–33.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [31] Fillingham, J. et al. Two-color cell array screen reveals interdependent roles for histone chaperones and a chromatin boundary regulator in histone gene repression. Mol. Cell 35, 340–351 (2009). source

      Not checked in the free run.

    • cites [32] Zunder, R. M. & Rine, J. Direct interplay among histones, histone chaperones, and a chromatin boundary protein in the control of histone gene expression. Mol. Cell Biol. 32, 4337–4349 (2012). source

      Not checked in the free run.

    • cites [33] Ferreira, M. E., Flaherty, K. & Prochasson, P. The Saccharomyces cerevisiae histone chaperone Rtt106 Mediates the cell cycle recruitment of SWI/SNF and RSC to the HIR-dependent histone genes. PLoS ONE 6, e21113 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mitochondrial dysfunction (e.g. loss of the mitochondrial genome) only stimulates Pdr3-dependent gene expression.

    “Such hyperactivation can be caused by gain-of-function (GOF) mutations in PDR1 or PDR314,15 or mitochondrial dysfunction (e.g. loss of the mitochondrial genome), the latter of which only stimulates Pdr3-dependent gene expression16.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Hallstrom, T. C. & Moye-Rowley, W. S. Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae. J. Biol. Chem. 275, 37347–37356 (2000). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Expression of PDR5 and the other PDR network genes in S. cerevisiae is regulated by Pdr1 and Pdr3, key transcription factors whose functions are partially redundant.

    “The expression of PDR5 and the other PDR network genes in S. cerevisiae is regulated by Pdr1 and Pdr3, key transcription factors whose functions are partially redundant10–12.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Balzi, E., Wang, M., Leterme, S., Van Dyck, L. & Goffeau, A. PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1. J. Biol. Chem. 269, 2206–2214 (1994). source

      Not checked in the free run.

    • cites [11] Katzmann, D. J., Burnett, P. E., Golin, J., Mahe, Y. & Moye-Rowley, W. S. Transcriptional control of the yeast PDR5 gene by the PDR3 gene product. Mol. Cell Biol. 14, 4653–4661 (1994).

      Not checked in the free run.

    • cites [12] Mahe, Y. et al. The ATP-binding cassette multidrug transporter Snq2 of Saccharomyces cerevisiae: a novel target for the transcription factors Pdr1 and Pdr3. Mol. Microbiol. 20, 109–117 (1996). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SWI/SNF localises to nucleosome-depleted regions (NDRs) in promoters and regulates the position of the transcription start site (TSS)-associated (or '+1') nucleosome critical for transcription initiation.

    “SWI/SNF localises to nucleosome-depleted regions (NDRs) in promoters and regulates the position of the transcription start site (TSS)-associated (or ‘+1’) nucleosome critical for transcription initiation20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Kubik, S. et al. Opposing chromatin remodelers control transcription initiation frequency and start site selection. Nat. Struct. Mol. Biol. 26, 744–754 (2019). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Histone chaperones and ATP-dependent chromatin-remodelling complexes are important for gene regulation because they regulate nucleosome dynamics at promoters, restricting or increasing promoter accessibility for recruitment of transcription factors and RNA polymerase II (Pol II).

    “Histone chaperones and ATP-dependent chromatin-remodelling complexes are accordingly important for gene regulation given they regulate nucleosome dynamics at promoters, restricting or increasing promoter accessibility for recruitment of transcription factors and RNA polymerase II (Pol II)19–23.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [19] Kubik, S. et al. Sequence-directed action of RSC remodeler and general regulatory factors modulates +1 nucleosome position to facilitate transcription. Mol. Cell 71, 89–102 e105 (2018). source

      Not checked in the free run.

    • cites [20] Kubik, S. et al. Opposing chromatin remodelers control transcription initiation frequency and start site selection. Nat. Struct. Mol. Biol. 26, 744–754 (2019). source

      Not checked in the free run.

    • cites [21] Rufiange, A., Jacques, P. E., Bhat, W., Robert, F. & Nourani, A. Genome-wide replication-independent histone H3 exchange occurs predominantly at promoters and implicates H3 K56 acetylation and Asf1. Mol. Cell 27, 393–405 (2007). source

      Not checked in the free run.

    • cites [22] Adkins, M. W., Howar, S. R. & Tyler, J. K. Chromatin disassembly mediated by the histone chaperone Asf1 is essential for transcriptional activation of the yeast PHO5 and PHO8 genes. Mol. Cell 14, 657–666 (2004). source

      Not checked in the free run.

    • cites [23] Korber, P. et al. The histone chaperone Asf1 increases the rate of histone eviction at the yeast PHO5 and PHO8 promoters. J. Biol. Chem. 281, 5539–5545 (2006). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Recruitment of transcription machinery to promoters is restricted by nucleosomes.

    “Recruitment of transcription machinery to promoters is restricted by nucleosomes19.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Kubik, S. et al. Sequence-directed action of RSC remodeler and general regulatory factors modulates +1 nucleosome position to facilitate transcription. Mol. Cell 71, 89–102 e105 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rtt106 localises at the promoters of three out of four histone gene pairs (HTA1-HTB1, HHT1-HHF1 and HHT2-HHF2, but not HTA2-HTB2) and restricts their transcription to S phase.

    “Rtt106 localises at the promoters of three out of four histone gene pairs (HTA1-HTB1, HHT1-HHF1 and HHT2-HHF2, but not HTA2-HTB2), and restricts their transcription to S phase, when new histone supply is required to package newly synthesised DNA31,32.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Fillingham, J. et al. Two-color cell array screen reveals interdependent roles for histone chaperones and a chromatin boundary regulator in histone gene repression. Mol. Cell 35, 340–351 (2009). source

      Not checked in the free run.

    • cites [32] Zunder, R. M. & Rine, J. Direct interplay among histones, histone chaperones, and a chromatin boundary protein in the control of histone gene expression. Mol. Cell Biol. 32, 4337–4349 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rtt106 regulates the activity of the histone gene promoters during the cell cycle in S. cerevisiae.

    “Apart from its role in histone deposition during replication and transcription elongation, Rtt106 regulates the activity of the histone gene promoters during the cell cycle in S. cerevisiae30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Eriksson, P. R., Ganguli, D., Nagarajavel, V. & Clark, D. J. Regulation of histone gene expression in budding yeast. Genetics 191, 7–20 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In C. glabrata, overexpression of drug transporter genes is caused by GOF mutations in the transcription factor Pdr1.

    “In C. glabrata also, overexpression of the drug transporter genes is caused by GOF mutations in the transcription factor Pdr19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Ferrari, S. et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 5, e1000268 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SWI/SNF modulates nucleosome position to regulate the expression of a subset of genes including stress-responsive genes.

    “SWI/SNF modulates nucleosome position to regulate the expression of a subset of genes including stress-responsive genes20,37–40.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [20] Kubik, S. et al. Opposing chromatin remodelers control transcription initiation frequency and start site selection. Nat. Struct. Mol. Biol. 26, 744–754 (2019). source

      Not checked in the free run.

    • cites [37] Sudarsanam, P., Iyer, V. R., Brown, P. O. & Winston, F. Whole-genome expression analysis of snf/swi mutants of Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 97, 3364–3369 (2000). source

      Not checked in the free run.

    • cites [38] Shivaswamy, S. & Iyer, V. R. Stress-dependent dynamics of global chromatin remodeling in yeast: dual role for SWI/SNF in the heat shock stress response. Mol. Cell Biol. 28, 2221–2234 (2008). source

      Not checked in the free run.

    • cites [39] Dutta, A. et al. Swi/Snf dynamics on stress-responsive genes is governed by competitive bromodomain interactions. Genes Dev. 28, 2314–2330 (2014). source

      Not checked in the free run.

    • cites [40] Gkikopoulos, T., Havas, K. M., Dewar, H. & Owen-Hughes, T. SWI/SNF and Asf1p cooperate to displace histones during induction of the saccharomyces cerevisiae HO promoter. Mol. Cell Biol. 29, 4057–4066 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hyperactivation of Pdr1 or Pdr3 is the main cause of overexpression of PDR5 leading to drug resistance.

    “Hyperactivation of Pdr1 or Pdr3 is the main cause of overexpression of PDR5 leading to drug resistance.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Meyers, S. et al. Interaction of the yeast pleiotropic drug resistance genes PDR1 and PDR5. Curr. Genet. 21, 431–436 (1992). source

      Not checked in the free run.

    • cites [15] Wolfger, H., Mahe, Y., Parle-McDermott, A., Delahodde, A. & Kuchler, K. The yeast ATP binding cassette (ABC) protein genes PDR10 and PDR15 are novel targets for the Pdr1 and Pdr3 transcriptional regulators. FEBS Lett. 418, 269–274 (1997). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Accessibility of gene promoters is a key factor in gene regulation.

    “Accessibility of gene promoters is a key factor in gene regulation17,18.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Rhee, H. S. & Pugh, B. F. Genome-wide structure and organization of eukaryotic pre-initiation complexes. Nature 483, 295–301 (2012). source

      Not checked in the free run.

    • cites [18] Lai, W. K. M. & Pugh, B. F. Understanding nucleosome dynamics and their links to gene expression and DNA replication. Nat. Rev. Mol. Cell Biol. 18, 548–562 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pdr1 and Pdr3 recognise the PDR responsive element (PDRE: 5′-TCCG(C/T)GGA-3′) present in promoters of the PDR network genes through their Zn(2)-Cys(6) finger DNA-binding domains.

    “Pdr1 and Pdr3 form a heterodimer or homodimers, which through their Zn(2)-Cys(6) finger DNA-binding domains13 recognise the PDR responsive element (PDRE: 5′-TCCG(C/T)GGA-3′) present in promoters of the PDR network genes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Mamnun, Y. M., Pandjaitan, R., Mahe, Y., Delahodde, A. & Kuchler, K. The yeast zinc finger regulators Pdr1p and Pdr3p control pleiotropic drug resistance (PDR) as homo- and heterodimers in vivo. Mol. Microbiol. 46, 1429–1440 (2002). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rtt106 recruitment to the histone promoters almost completely depends on Asf1, HIR and acetylation of histone H3 at K56 (H3K56Ac), and is limited by Yta7.

    “Rtt106 recruitment to the histone promoters almost completely depends on Asf1, HIR and acetylation of histone H3 at K56 (H3K56Ac), and is limited by Yta7, a bromodomain- and AAA-ATPase domain-containing boundary protein31,32,35.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [31] Fillingham, J. et al. Two-color cell array screen reveals interdependent roles for histone chaperones and a chromatin boundary regulator in histone gene repression. Mol. Cell 35, 340–351 (2009). source

      Not checked in the free run.

    • cites [32] Zunder, R. M. & Rine, J. Direct interplay among histones, histone chaperones, and a chromatin boundary protein in the control of histone gene expression. Mol. Cell Biol. 32, 4337–4349 (2012). source

      Not checked in the free run.

    • cites [35] Kurat, C. F. et al. Restriction of histone gene transcription to S phase by phosphorylation of a chromatin boundary protein. Genes Dev. 25, 2489–2501 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Rtt106 may be generally important for the expression of transporter genes, though some effects could be indirect.

    “Rtt106 may therefore be generally important for the expression of transporter genes—even though we did not identify Rtt106 bound at all the gene promoters affected, suggesting some effects could be indirect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Mildly deregulated transcription initiation occurs fairly ubiquitously in rtt106Δ, resulting in a readily apparent fold increase of mRNA with low abundance but a less obvious effect on mRNA with a high level of expression.

    “We suspect that mildly deregulated transcription initiation occurs fairly ubiquitously in rtt106Δ, resulting in a readily apparent fold increase of mRNA with low abundance, but a less obvious effect on mRNA with a high level of expression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Atypically wide NDRs possibly reflect that inducible gene promoters are occupied by specific transcriptional regulators.

    “possibly reflecting the fact that inducible gene promoters are occupied by specific transcriptional regulators.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Expression of the PDR network genes can be induced by many substances, including the antifungal azole drug ketoconazole.

    “Expression of the PDR network genes can be induced by many substances, including the antifungal azole drug ketoconazole7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Thakur, J. K. et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452, 604–609 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The decrease of non-PDR genes in pdr3Δ may represent an indirect consequence of PDR network gene dysregulation.

    “We suspect that this may represent an indirect consequence of PDR network gene dysregulation, since it is unlikely that such genes are directly controlled by Pdr3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Rtt106 generally upregulates the expression of the PDR network genes, in contrast to its repressive role in histone gene expression.

    “These results suggest that Rtt106 generally upregulates the expression of the PDR network genes, in contrast to its repressive role in histone gene expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    HIR and Yta7 contribute to Rtt106 recruitment at the promoters of both the PDR network genes and the histone genes, but their specific effects differ somewhat in the two classes of promoters.

    “Taken together, our results show that HIR and Yta7 contribute to Rtt106 recruitment at the promoters of both the PDR network genes and the histone genes, but their specific effects differ somewhat in the two classes of promoters.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The increased mRNA in rtt106Δ may reflect increased transcription initiation caused by defective histone deposition or increased nucleosome spacing.

    “This may reflect increased transcription initiation that could be caused by defective histone deposition or increased nucleosome spacing in rtt106Δ26,27,29.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] Imbeault, D., Gamar, L., Rufiange, A., Paquet, E. & Nourani, A. The Rtt106 histone chaperone is functionally linked to transcription elongation and is involved in the regulation of spurious transcription from cryptic promoters in yeast. J. Biol. Chem. 283, 27350–27354 (2008). source

      Not checked in the free run.

    • cites [27] Zunder, R. M., Antczak, A. J., Berger, J. M. & Rine, J. Two surfaces on the histone chaperone Rtt106 mediate histone binding, replication, and silencing. Proc. Natl Acad. Sci. USA 109, E144–E153 (2012). source

      Not checked in the free run.

    • cites [29] Lombardi, L. M., Davis, M. D. & Rine, J. Maintenance of nucleosomal balance in cis by conserved AAA-ATPase Yta7. Genetics 199, 105–116 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Rtt106 generally binds the promoters of the PDR network genes in a common manner designated Type A, fully dependent on Pdr1/3 and partially on HIR, and limited by Yta7.

    “indicating that Rtt106 generally binds the promoters of the PDR network genes in a common manner that we designate ‘Type A’ i.e. fully dependent on Pdr1/3 and partially on HIR, and limited by Yta7.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The difference in histone gene effects may reflect the fact that we prepared RNA from asynchronous cells rather than cells at specific cell-cycle stages.

    “This difference may reflect the fact that we prepared RNA from asynchronous cells rather than cells at specific cell-cycle stages31,32.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Fillingham, J. et al. Two-color cell array screen reveals interdependent roles for histone chaperones and a chromatin boundary regulator in histone gene repression. Mol. Cell 35, 340–351 (2009). source

      Not checked in the free run.

    • cites [32] Zunder, R. M. & Rine, J. Direct interplay among histones, histone chaperones, and a chromatin boundary protein in the control of histone gene expression. Mol. Cell Biol. 32, 4337–4349 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    At the histone promoters, SWI/SNF is recruited by Rtt106, probably through direct physical interactions.

    “However, at the histone promoters, SWI/SNF is recruited by Rtt106, probably through direct physical interactions33.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Ferreira, M. E., Flaherty, K. & Prochasson, P. The Saccharomyces cerevisiae histone chaperone Rtt106 Mediates the cell cycle recruitment of SWI/SNF and RSC to the HIR-dependent histone genes. PLoS ONE 6, e21113 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Increased recruitment of Rtt106 to the PDR5 promoter in pdr1Δ may reflect an increase of Pdr3 at the PDR5 promoter in the absence of Pdr1.

    “Increased recruitment of Rtt106 to the PDR5 promoter in pdr1Δ may reflect an increase of Pdr3 at the PDR5 promoter in the absence of Pdr1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    SWI/SNF regulates PDR5 expression by acting directly at the PDR5 promoter as well as through regulating gene expression of the transcription factor PDR3.

    “Taken together, these results and the evidence of SWI/SNF binding to the PDR5 promoter suggest that SWI/SNF regulates PDR5 expression by acting directly at the PDR5 promoter as well as through regulating gene expression of the transcription factor PDR3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Pdr3 and Rtt106 are more critical for resistance to continuous high doses of azole antifungals than Pdr1, and Pdr1 function alone cannot mediate resistance to high doses at the condition tested.

    “This finding suggests that Pdr3 and Rtt106 are more critical for resistance to continuous high doses of azole antifungals than Pdr1; and that Pdr1 function alone cannot mediate resistance to high doses at the condition tested.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Rtt106 regulates PDR5 expression by acting directly at the PDR5 promoter, not only indirectly through regulating PDR3 expression.

    “Our results nonetheless indicate that Rtt106 regulates PDR5 expression by acting directly at the PDR5 promoter (and not only indirectly through regulating PDR3 expression) as a ~50% reduction of Pdr3 binding at the PDR5 promoter in rtt106Δ cannot alone explain why rtt106Δ and pdr3Δ mutants have similar effects on PDR5 expression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The unexpected results might reflect that PDR3 undergoes auto-activation of its own transcription, while PDR1 does not.

    “Although these are unexpected results since Pdr1 is critical for drug-induced expression of PDR5, this observation might reflect the fact that PDR3 undergoes auto-activation of its own transcription45, while PDR1 does not.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Delahodde, A., Delaveau, T. & Jacq, C. Positive autoregulation of the yeast transcription factor Pdr3p, which is involved in control of drug resistance. Mol. Cell Biol. 15, 4043–4051 (1995). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Rtt106 recruitment to the PDR5 promoter depends on Pdr3, and not Pdr1.

    “Rtt106 recruitment to the PDR5 promoter, therefore, depends on Pdr3, and not Pdr1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    SWI/SNF is an essential upregulator of the PDR network genes both for basal and drug-induced expression.

    “These results suggest that SWI/SNF is an essential upregulator of the PDR network genes both for basal and drug-induced expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Rtt106 regulates basal expression of PDR5 via Pdr3 and also mediates drug resistance.

    “Overall, these results suggest that Rtt106 regulates basal expression of PDR5 via Pdr3 and also mediates drug resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Rtt106 and Pdr3 are essential for basal expression of the PDR network genes during growth without antifungal agents, while Pdr1 mediates their azole-induced, transient expression.

    “Overall, the results in Fig. 3 suggest that Rtt106 and Pdr3 are essential for basal expression of the PDR network genes during growth without antifungal agents, while Pdr1 mediates their azole-induced, transient expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    C. albicans Rtt106 and C. albicans SWI/SNF affect hyphae formation, which indirectly influences drug tolerance and pathogenicity.

    “C. albicans Rtt106 and C. albicans SWI/SNF affect hyphae formation56,57, which indirectly influences drug tolerance and pathogenicity.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Jenull, S. et al. The Candida albicans HIR histone chaperone regulates the yeast-to-hyphae transition by controlling the sensitivity to morphogenesis signals. Sci. Rep. 7, 8308 (2017). source

      Not checked in the free run.

    • cites [57] Mao, X., Cao, F., Nie, X., Liu, H. & Chen, J. The Swi/Snf chromatin remodeling complex is essential for hyphal development in Candida albicans. FEBS Lett. 580, 2615–2622 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    CgRtt106 and CgSWI/SNF are important for the expression of the PDR network genes in response to ketoconazole in C. glabrata, and therefore for its resistance to azole antifungals.

    “Finally, we observed that CgRtt106 and CgSWI/SNF are important for the expression of the PDR network genes in response to ketoconazole in C. glabrata, and therefore for its resistance to azole antifungals, highlighting those factors as potential therapeutic targets to combat antifungal resistance of C. glabrata.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    At promoters, human HIRA and ASF1a essentially localise to nucleosome-free TSSs.

    “Interestingly, at promoters, human HIRA and ASF1a essentially localise to nucleosome-free TSSs52, reminiscent of our findings that yeast Rtt106 is enriched at wider nucleosome-free regions upstream of TSSs (Fig. 2g).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Pchelintsev, N. A. et al. Placing the HIRA histone chaperone complex in the chromatin landscape. Cell Rep. 3, 1012–1019 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    SWI/SNF plays a crucial role in both Pdr1- and Pdr3-mediated expression of the PDR network genes and confers azole drug resistance.

    “Furthermore, we showed that SWI/SNF plays a crucial role in both Pdr1- and Pdr3-mediated expression of the PDR network genes and confers azole drug resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Rtt106 and SWI/SNF are general regulators of the PDR network genes and confer drug resistance in S. cerevisiae, and their roles are largely conserved in the pathogenic fungus C. glabrata.

    “Our findings in this study suggest that Rtt106 and SWI/SNF are general regulators of the PDR network genes and confer drug resistance in S. cerevisiae, and their roles are largely conserved in the pathogenic fungus C. glabrata.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The experiments for confirming the expression of a series of epitope-tagged Pdr3 (Supplementary Fig. 3b, c) were performed once with at least two different isolates which showed similar results.

    “The experiments for confirming the expression of a series of epitope-tagged Pdr3 (Supplementary Fig. 3b, c) were performed once with at least two different isolates which showed similar results.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Rtt106 and some SWI/SNF subunits are fungal-specific, and these factors offer attractive therapeutic targets to combat antifungal drug resistance in C. glabrata and potentially other Candida species.

    “Since Rtt106 and some SWI/SNF subunits are fungal-specific, these factors offer attractive therapeutic targets to combat antifungal drug resistance in C. glabrata and potentially other Candida species.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Rtt106 and some SWI/SNF subunits are fungal-specific.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    For Northern blot and GST pull-down analyses and testing protein level of Pdr5 (Fig. 4b), each experiment was repeated three times independently with similar results, and one representative data of the replicates are presented.

    “For Northern blot and GST pull-down analyses and testing protein level of Pdr5 (Fig. 4b), each experiment was repeated three times independently with similar results, and one representative data of the replicates are presented.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Mass spectrometry analysis of isolated minichromosome was performed once; proteins quantified at least 5 ratio counts were presented, allowing reliable quantification of proteins in the sample analysed.

    “Mass spectrometry analysis of isolated minichromosome was performed once and therefore proteins quantified at least 5 ratio counts were presented, allowing reliable quantification of proteins in the sample analysed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In human, histone chaperones HIRA and ASF1a localise at active promoters where BRG1, a human SWI/SNF complex subunit, also localises.

    “In human, histone chaperones HIRA and ASF1a localise at active promoters where BRG1, a human SWI/SNF complex subunit, also localises52.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Pchelintsev, N. A. et al. Placing the HIRA histone chaperone complex in the chromatin landscape. Cell Rep. 3, 1012–1019 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Rtt106 drives Pdr3-mediated expression of PDR5 and confers resistance to azole antifungals in S. cerevisiae.

    “In S. cerevisiae, Rtt106 is recruited to the promoter of the multidrug transporter gene PDR5 exclusively through the transcription factor Pdr3, which drives Pdr3-mediated expression of PDR5, and confers resistance to azole antifungals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Rtt106 and SWI/SNF upregulate PDR network gene expression and confer drug resistance in S. cerevisiae and C. glabrata.

    “In this study, we found that Rtt106 and SWI/SNF upregulate PDR network gene expression and confer drug resistance in S. cerevisiae and C. glabrata.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    C. albicans SWI/SNF mediates overexpression of the drug efflux protein Mdr1 due to GOF mutations in the transcription factor Mrr1, thus conferring fluconazole resistance.

    “C. albicans SWI/SNF mediates overexpression of the drug efflux protein Mdr1 due to GOF mutations in the transcription factor Mrr1, thus conferring fluconazole resistance55.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Liu, Z. & Myers, L. C. Candida albicans Swi/Snf and mediator complexes differentially regulate Mrr1-induced MDR1 expression and fluconazole resistance. Antimicrob. Agents Chemother. 61, e01344–e01317 (2017).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A strict target FDR of 0.01 was used for the decoy database search in mass spectrometry data analysis.

    “A strict target FDR of 0.01 for the decoy database search was used.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HIRA mediates the replacement of canonical H3 with the H3.3 variant at promoters.

    “HIRA mediates the replacement of canonical H3 with the H3.3 variant at promoters52, and continuous H3.3 exchange has been proposed to keep these sites transiently exposed, allowing transcription factors to access their binding sites53.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Pchelintsev, N. A. et al. Placing the HIRA histone chaperone complex in the chromatin landscape. Cell Rep. 3, 1012–1019 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GOF mutations in CgPdr1 make it hyperactive, resulting in high multidrug transporter expression and thus driving antifungal resistance in clinical isolates of C. glabrata.

    “GOF mutations in CgPdr1 make it hyperactive, resulting in high multidrug transporter expression and thus driving antifungal resistance in clinical isolates of C. glabrata9,54.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Ferrari, S. et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 5, e1000268 (2009). source

      Not checked in the free run.

    • cites [54] Tsai, H. F., Krol, A. A., Sarti, K. E. & Bennett, J. E. Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob. Agents Chemother. 50, 1384–1392 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    ERCC spike-in controls were added to the RNA samples to be used as internal controls.

    “ERCC (External RNA Controls Consortium) spike-in controls were added to the RNA samples to be used as internal controls.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Histone chaperone Asf1 mediates nucleosome disassembly from the PHO5 promoter for its activation in yeast.

    “It has been reported that histone chaperone Asf1 mediates nucleosome disassembly from the PHO5 promoter for its activation in yeast22,23.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Adkins, M. W., Howar, S. R. & Tyler, J. K. Chromatin disassembly mediated by the histone chaperone Asf1 is essential for transcriptional activation of the yeast PHO5 and PHO8 genes. Mol. Cell 14, 657–666 (2004). source

      Not checked in the free run.

    • cites [23] Korber, P. et al. The histone chaperone Asf1 increases the rate of histone eviction at the yeast PHO5 and PHO8 promoters. J. Biol. Chem. 281, 5539–5545 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rapid histone turnover occurs at other sites where Rtt106 is enriched, including tRNA and snoRNA.

    “Interestingly, in S. cerevisiae rapid histone turnover also has been shown to occur at other sites where Rtt106 is enriched, including tRNA and snoRNA51 (Fig. 2e and Supplementary Fig. 1d).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Dion, M. F. et al. Dynamics of replication-independent histone turnover in budding yeast. Science 315, 1405–1408 (2007). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    C. glabrata has a single PDRE-binding transcription factor CgPdr1 that shares homology almost equally with S. cerevisiae Pdr1 and Pdr3 and possesses a blend of their properties.

    “A major difference between C. glabrata and S. cerevisiae in the PDR network regulation is that C. glabrata has the single PDRE-binding transcription factor called CgPdr1 which shares homology almost equally with the S. cerevisiae Pdr1 and Pdr3 proteins, and possesses a blend of the properties of each50.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Paul, S., Schmidt, J. A. & Moye-Rowley, W. S. Regulation of the CgPdr1 transcription factor from the pathogen Candida glabrata. Eukaryot. Cell 10, 187–197 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    CgRtt106 and CgSWI/SNF drive the expression of the PDR network genes in C. glabrata, with contributions limited to drug-induced expression.

    “These results suggest that CgRtt106 and CgSWI/SNF drive the expression of the PDR network genes in C. glabrata, although their contributions appear limited to drug-induced expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CgRtt106 and CgSWI/SNF upregulate the expression of multidrug transporter genes and confer antifungal resistance in C. glabrata.

    “Taken together, these results demonstrate that CgRtt106 and CgSWI/SNF upregulate the expression of multidrug transporter genes and confer antifungal resistance in C. glabrata.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The inserted sequences were confirmed by sequencing.

    “The inserted sequences were confirmed by sequencing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Minichromosome isolation and purification of the SWI/SNF complex followed by SYPRO Ruby staining (Supplementary Fig. 6a, b) were repeated three times independently with similar results; data from one representative experiment are shown.

    “Minichromosome isolation and purification of the SWI/SNF complex followed by SYPRO Ruby staining (Supplementary Fig. 6a, b) were repeated three times independently with similar results; data from one representative experiment are shown.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    During logarithmic growth, Rtt106 and SWI/SNF bind to promoters of the PDR network genes mainly through Pdr3 and cooperatively drive Pdr3-dependent expression.

    “Taken together, we propose that during logarithmic growth Rtt106 and SWI/SNF bind to promoters of the PDR network genes mainly through Pdr3, and cooperatively drive Pdr3-dependent expression; while in response to ketoconazole SWI/SNF mediates Pdr1-dependent-drug-induced expression of the PDR network genes in S. cerevisiae (Fig. 6h).”
    Quote in the paperSubstantial claim
99 of 99

  • The paper relies on this without support.

    Ketoconazole stimulates only Pdr1 in the condition tested.

    “which stimulates only Pdr1 in the condition tested”

  • The paper relies on this without support.

    Rtt106 and some SWI/SNF subunits are fungal-specific.

    “Since Rtt106 and some SWI/SNF subunits are fungal-specific”

  • The paper relies on this without support.

    The TSS-associated +1 nucleosome is critical for transcription initiation.

    “which is critical for transcription initiation”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Rtt106 and some SWI/SNF subunits may serve as promising therapeutic targets to overcome antifungal resistance in C. glabrata.

    “Notably, Rtt106 and some SWI/SNF subunits are fungal-specific and thus may serve as promising therapeutic targets to overcome antifungal resistance in this important pathogen99.”

    From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [99]

  • In C. glabrata, the SWI/SNF complex and the histone chaperone Rtt106 mediate azole resistance by driving the expression of multidrug transporter genes including CDR1.

    “In C. glabrata, the SWI/SNF complex, along with the histone chaperone Rtt106, mediate azole resistance by driving the expression of the multidrug transporter genes, including CDR199.”

    From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [99]

  • Rtt106 and some SWI/SNF subunits are fungal-specific.

    “Notably, Rtt106 and some SWI/SNF subunits are fungal-specific and thus may serve as promising therapeutic targets to overcome antifungal resistance in this important pathogen99.”

    From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [99]

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Authors
Nikolov, V. N., Malavia, D., & Kubota, T.
Affiliations
University of Aberdeen (GB)
Corresponding author
Kubota, Takashi
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-04-12
Volume
13
Issue
1
Pages
1968-1968
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-29591-z
PMC
PMC9005695
OpenAlex
W4223601276
Semantic Scholar
75c5ac0e730e0ca6b6cb24b635efaeac3164c056
Cited by
16
References
73
Citations by year
2026: 3 · 2025: 3 · 2024: 7 · 2023: 2 · 2022: 1
FWCI
1.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Wellcome Trust (097377/Z/11/Z)
  • RCUK | Medical Research Council (L019698/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
histone chaperone, PDR1, antifungal resistance, antifungal drug response, Candida glabrata, Saccharomyces cerevisiae, gene expression regulation, transcriptional regulation, therapeutic target
MeSH terms
Antifungal Agents, Drug Resistance, Saccharomyces cerevisiae, Transcription Factors, Molecular Chaperones, Saccharomyces cerevisiae Proteins, Histone Chaperones

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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