Deregulation of the 19S proteasome complex increases yeast resistance to 4-NQO and oxidative stress via upregulation of Rpn4- and proteasome-dependent stress responsive genes

Карпов, Д. С.; Spasskaya, D. S.; Nadolinskaia, Nonna I.; Tutyaeva, Vera V.; Lysov, Yuriy P.; Карпов, В.Л.

doi:10.1093/femsyr/foz002

Cited by 10 publications

(17 citation statements)

References 54 publications

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“…In contrast, RPT5 deregulation in the YRL strain led to increased 20S proteasome activity ( Figure 1 b). This result can be explained by the increased expression of 20S proteasome genes due to Rpn4 stabilization, as we previously showed [ 24 ]. Despite differences in 20S proteasome activity, all the mutant strains exhibited defects in 26S proteasome activity—they accumulated polyubiquitinated proteins upon heat shock ( Figure 1 c), and showed sensitivity to classic proteotoxic stresses such as heat shock and exposure to the toxic proline analogue L-azetidine-2-carboxylic acid, thus displaying impaired proteasome function ( Figure 1 d).…”

Section: Resultssupporting

confidence: 70%

“…We showed earlier that an impaired Rpn4-dependent regulation of genes encoding essential subunits of 20S proteolytic ( PRE1 in the YPL strain) [ 19 ] or 19S regulatory ( RPT5 or RPT3 in the YRL or mRPT3 strain) [ 24 ] proteasome subcomplexes increases cell viability during acute and chronic exposure to DNA-damaging agents, such as MMS and 4-NQO. In this work, we obtained strains bearing PACE mutations in the promoters of both the PRE1 and RPT5 proteasomal genes to deregulate both 20S and 19S proteasome subcomplexes (YPRL strain, Figure 1 a).…”

Section: Resultsmentioning

confidence: 99%

“…These data suggest that both the proteasome and Rpn4 are positive regulators of DNA repair processes. Paradoxically, proteasome dysfunction, caused by inhibitors [ 19 ], mutations in proteasomal genes [ 21 , 22 , 23 ] or decreased expressions of essential proteasomal genes [ 19 , 24 ], leads to yeast hyper-resistance to DNA damage induced by camptothecin, 4-nitroquinoline-1-oxide (4-NQO) or methyl methanesulfonate (MMS). Although the deletion of the RPN4 gene was also found to cause proteasome dysfunction, the mutant strains were sensitive to all DNA-damaging agents tested [ 15 , 16 , 17 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

Spasskaya

Nadolinskaia

Tutyaeva

et al. 2020

IJMS

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Environmental and intracellular factors often damage DNA, but multiple DNA repair pathways maintain genome integrity. In yeast, the 26S proteasome and its transcriptional regulator and substrate Rpn4 are involved in DNA damage resistance. Paradoxically, while proteasome dysfunction may induce hyper-resistance to DNA-damaging agents, Rpn4 malfunction sensitizes yeasts to these agents. Previously, we proposed that proteasome inhibition causes Rpn4 stabilization followed by the upregulation of Rpn4-dependent DNA repair genes and pathways. Here, we aimed to elucidate the key Rpn4 targets responsible for DNA damage hyper-resistance in proteasome mutants. We impaired the Rpn4-mediated regulation of candidate genes using the CRISPR/Cas9 system and tested the sensitivity of mutant strains to 4-NQO, MMS and zeocin. We found that the separate or simultaneous deregulation of 19S or 20S proteasome subcomplexes induced MAG1, DDI1, RAD23 and RAD52 in an Rpn4-dependent manner. Deregulation of RAD23, DDI1 and RAD52 sensitized yeast to DNA damage. Genetic, epigenetic or dihydrocoumarin-mediated RAD52 repression restored the sensitivity of the proteasome mutants to DNA damage. Our results suggest that the Rpn4-mediated overexpression of DNA repair genes, especially RAD52, defines the DNA damage hyper-resistant phenotype of proteasome mutants. The developed yeast model is useful for characterizing drugs that reverse the DNA damage hyper-resistance phenotypes of cancers.

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Section: Resultssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

Spasskaya

Nadolinskaia

Tutyaeva

et al. 2020

IJMS

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“…Some mechanisms of resistance to 4-NQO have been characterized in S. cerevisiae and could vary with respect to hybrids, for instance through the perturbation of the proteasome (Karpov et al, 2019) and pathways involved in multi-drug resistance transporters (Rong-Mullins et al, 2018).…”

Section: Accepted Articlementioning

confidence: 99%

Interspecific hybrids show a reduced adaptive potential under DNA damaging conditions

Bautista

Marsit

Landry

2020

Evolutionary Applications

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Hybridization may increase the probability of adaptation to extreme stresses. This advantage could be caused by an increased genome plasticity in hybrids, which could accelerate the search for adaptive mutations. High ultraviolet (UV) radiation is a particular challenge in terms of adaptation because it affects the viability of organisms by directly damaging DNA, while also challenging future generations by increasing mutation rate. Here we test if hybridization accelerates adaptive evolution in response to DNA damage, using yeast as a model. We exposed 180 populations of hybrids between species (Saccharomyces cerevisiae and Saccharomyces paradoxus) and their parental strains to UV mimetic and control conditions for approximately 100 generations. Although we found that adaptation occurs in both hybrids and parents, hybrids achieved a lower rate of adaptation, contrary to our expectations. Adaptation to DNA damage conditions comes with a large and similar cost for parents and hybrids, suggesting that this cost is not responsible for the lower adaptability of hybrids. We suggest that the lower Accepted Article This article is protected by copyright. All rights reserved adaptive potential of hybrids in this condition may result from the interaction between DNA damage and the inherent genetic instability of hybrids.

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“…It would also be useful to identify the mechanistic basis of adaptation to UV mimetic chemicals in hybrids and parental species, as it is possible that hybrids do not have access to the same adaptive mutations as parental species. Some mechanisms of resistance have been characterized in S. cerevisiae and could vary with respect to hybrids, for instance through the perturbation of the proteasome (Karpov et al 2019) and pathways involved in multi-drug resistance transporters (Rong-Mullins et al 2018) .…”

Section: Discussionmentioning

confidence: 99%

Interspecific Hybrids Show a Reduced Adaptive Potential Under DNA Damaging Conditions

Bautista

Marsit

Landry

2020

Preprint

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AbstractHybridization may increase the probability of adaptation to extreme stresses. This advantage could be caused by an increased genome plasticity in hybrids, which could accelerate the search for adaptive mutations. High ultraviolet (UV) radiation is a particular challenge in terms of adaptation because it affects the viability of organisms by directly damaging DNA, while also challenging future generations by increasing mutation rate. Here we test if hybridization accelerates adaptive evolution in response to DNA damage, using yeast as a model. We exposed 180 populations of hybrids between species (Saccharomyces cerevisiae and Saccharomyces paradoxus) and their parental strains to UV mimetic and control conditions for approximately 100 generations. Although we found that adaptation occurs in both hybrids and parents, hybrids achieved a lower rate of adaptation, contrary to our expectations. Adaptation to DNA damage conditions comes with a large and similar cost for parents and hybrids, suggesting that this cost is not responsible for the lower adaptability of hybrids. We suggest that the lower adaptive potential of hybrids in this condition may result from the interaction between DNA damage and the inherent genetic instability of hybrids.

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Deregulation of the 19S proteasome complex increases yeast resistance to 4-NQO and oxidative stress via upregulation of Rpn4- and proteasome-dependent stress responsive genes

Cited by 10 publications

References 54 publications

Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

Interspecific hybrids show a reduced adaptive potential under DNA damaging conditions

Interspecific Hybrids Show a Reduced Adaptive Potential Under DNA Damaging Conditions

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