Proteasome inhibition enhances resistance to DNA damage via upregulation of Rpn4‐dependent DNA repair genes

Карпов, Д. С.; Spasskaya, D. S.; Tutyaeva, Vera V.; Миронов, А.; Карпов, В.Л.

doi:10.1016/j.febslet.2013.08.007

Cited by 27 publications

(36 citation statements)

References 45 publications

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“…The transcription factor Rpn4 of S. cerevisiae is involved in regulation of DNA repair (17,18) and functions as a transcriptional activator of 26S proteasomal subunits (13,19) a All the strains were grown in TM-G for 16 h, followed by 4 h in MM-X. Differentially expressed genes in the ΔflbA and Δfum21 strains can be found in references 9 and 10. b When no function of the gene could be inferred from MycoCosm, GO/KEGG terms, and a blastp search, the functional annotation is given as "no annotation."…”

Section: Discussionmentioning

confidence: 99%

FlbA-Regulated Gene rpnR Is Involved in Stress Resistance and Impacts Protein Secretion when Aspergillus niger Is Grown on Xylose

Aerts

Bergh

Post

et al. 2019

Appl Environ Microbiol

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Proteins are secreted throughout the mycelium of Aspergillus niger except for the sporulating zone. A link between sporulation and repression of protein secretion was underlined by the finding that inactivation of the sporulation gene flbA results in mycelial colonies that secrete proteins throughout the colony. However, ΔflbA strain hyphae also lyse and have thinner cell walls. This pleiotropic phenotype is associated with differential expression of 36 predicted transcription factor genes, one of which, rpnR, was inactivated in this study. Sporulation, biomass, and secretome complexity were not affected in the ΔrpnR deletion strain of the fungus. In contrast, ribosomal subunit expression and protein secretion into the medium were reduced when A. niger was grown on xylose. Moreover, the ΔrpnR strain showed decreased resistance to H 2 O 2 and the proteotoxic stress-inducing agent dithiothreitol. Taking the data together, RpnR is involved in proteotoxic stress resistance and impacts protein secretion when A. niger is grown on xylose. IMPORTANCE Aspergillus niger secretes a large amount and diversity of industrially relevant enzymes into the culture medium. This makes the fungus a widely used industrial cell factory. For instance, carbohydrate-active enzymes of A. niger are used in biofuel production from lignocellulosic feedstock. These enzymes represent a major cost factor in this process. Higher production yields could substantially reduce these costs and therefore contribute to a more sustainable economy and less dependence on fossil fuels. Enzyme secretion is inhibited in A. niger by asexual reproduction. The sporulation protein FlbA is involved in this process by impacting the expression of 36 predicted transcription factor genes. Here, we show that one of these predicted transcriptional regulators, RpnR, regulates protein secretion and proteotoxic stress resistance. The gene is thus an interesting target to improve enzyme production in A. niger.

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Section: Discussionmentioning

confidence: 99%

FlbA-Regulated Gene rpnR Is Involved in Stress Resistance and Impacts Protein Secretion when Aspergillus niger Is Grown on Xylose

Aerts

Bergh

Post

et al. 2019

Appl Environ Microbiol

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“…Msn2 and Msn4 are the key regulators of the general stress response, while Yap1 is involved in the oxidative stress response and also in specific cases of drug resistance, and Sfp1 is involved in ribosome biogenesis and, indirectly, in resistance to many stress conditions. The regulatory associations involving Rpn4, a transcription factor that controls proteosomal genes and that is implicated in the oxidative stress response and DNA repair (Jelinsky et al, 2000; Karpov et al, 2013), in particular induced by the genotoxic agent MMS (Spasskaya et al, 2014), are also of interest. Rpn4 has been shown to regulate 43% of all DHA1/DAG genes, including the 4 genes ( ARN1 , ATR1 , AQR1 , and FLR1 ) whose expression and/or localization was found to change in response to MMS treatment leading to replicative stress (Tkach et al, 2012).…”

Section: Clues On the Functional Analysis Of Dha1/dag Transporters Bamentioning

confidence: 99%

MFS transporters required for multidrug/multixenobiotic (MD/MX) resistance in the model yeast: understanding their physiological function through post-genomic approaches

Santos¹,

Teixeira²,

Dias³

et al. 2014

Front. Physiol.

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Multidrug/Multixenobiotic resistance (MDR/MXR) is a widespread phenomenon with clinical, agricultural and biotechnological implications, where MDR/MXR transporters that are presumably able to catalyze the efflux of multiple cytotoxic compounds play a key role in the acquisition of resistance. However, although these proteins have been traditionally considered drug exporters, the physiological function of MDR/MXR transporters and the exact mechanism of their involvement in resistance to cytotoxic compounds are still open to debate. In fact, the wide range of structurally and functionally unrelated substrates that these transporters are presumably able to export has puzzled researchers for years. The discussion has now shifted toward the possibility of at least some MDR/MXR transporters exerting their effect as the result of a natural physiological role in the cell, rather than through the direct export of cytotoxic compounds, while the hypothesis that MDR/MXR transporters may have evolved in nature for other purposes than conferring chemoprotection has been gaining momentum in recent years. This review focuses on the drug transporters of the Major Facilitator Superfamily (MFS; drug:H+ antiporters) in the model yeast Saccharomyces cerevisiae. New insights into the natural roles of these transporters are described and discussed, focusing on the knowledge obtained or suggested by post-genomic research. The new information reviewed here provides clues into the unexpectedly complex roles of these transporters, including a proposed indirect regulation of the stress response machinery and control of membrane potential and/or internal pH, with a special emphasis on a genome-wide view of the regulation and evolution of MDR/MXR-MFS transporters.

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“…It was reported that inhibition of proteasome activity impairs DNA repair and DNA damage-induced apoptosis in cancer cells [7]. Other studies demonstrated that proteasome plays rather a negative role in DDR [8]. Evidence suggested that proteasome might regulate DDR either indirectly via availability of ubiquitin pool or directly by deubiquitinating and degrading DDR proteins.…”

Section: Introductionmentioning

confidence: 99%

Loss of Urokinase Receptor Sensitizes Cells to DNA Damage and Delays DNA Repair

et al. 2014

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DNA damage induced by numerous exogenous or endogenous factors may have irreversible consequences on the cell leading to cell cycle arrest, senescence and cell death. The DNA damage response (DDR) is powerful signaling machinery triggered in response to DNA damage, to provide DNA damage recognition, signaling and repair. Most anticancer drugs induce DNA damage, and DNA repair in turn attenuates therapeutic efficiency of those drugs. Approaches delaying DNA repair are often used to increase efficiency of treatment. Recent data show that ubiquitin-proteasome system is essential for signaling and repair of DNA damage. However, mechanisms providing regulation of proteasome intracellular localization, activity, and recruitment to DNA damage sites are elusive. Even less investigated are the roles of extranuclear signaling proteins in these processes. In this study, we report the involvement of the serine protease urokinase-type plasminogen activator receptor (uPAR) in DDR-associated regulation of proteasome. We show that in vascular smooth muscle cells (VSMC) uPAR activates DNA single strand break repair signaling pathway. We provide evidence that uPAR is essential for functional assembly of the 26S proteasome. We further demonstrate that uPAR mediates DNA damage-induced phosphorylation, nuclear import, and recruitment of the regulatory subunit PSMD6 to proteasome. We found that deficiency of uPAR and PSMD6 delays DNA repair and leads to decreased cell survival. These data may offer new therapeutic approaches for diseases such as cancer, cardiovascular and neurodegenerative disorders.

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Proteasome inhibition enhances resistance to DNA damage via upregulation of Rpn4‐dependent DNA repair genes

Cited by 27 publications

References 45 publications

FlbA-Regulated Gene rpnR Is Involved in Stress Resistance and Impacts Protein Secretion when Aspergillus niger Is Grown on Xylose

FlbA-Regulated Gene rpnR Is Involved in Stress Resistance and Impacts Protein Secretion when Aspergillus niger Is Grown on Xylose

MFS transporters required for multidrug/multixenobiotic (MD/MX) resistance in the model yeast: understanding their physiological function through post-genomic approaches

Loss of Urokinase Receptor Sensitizes Cells to DNA Damage and Delays DNA Repair

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