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Effect of Ferulic Acid, a Phenolic Inducer of Fungal Laccase, on 26S Proteasome Activities In Vitro
Open AccessArticle

Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

1
Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, 119991 Moscow, Russia
2
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(21), 8097; https://doi.org/10.3390/ijms21218097
Received: 4 September 2020 / Revised: 22 October 2020 / Accepted: 29 October 2020 / Published: 30 October 2020
(This article belongs to the Special Issue Proteostasis and Proteasome Inhibitors 2.0)
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. View Full-Text
Keywords: 26S proteasome; Rpn4; DNA repair; RAD52; RAD23; DDI1; CRISPR/Cas9 26S proteasome; Rpn4; DNA repair; RAD52; RAD23; DDI1; CRISPR/Cas9
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Spasskaya, D.S.; Nadolinskaia, N.I.; Tutyaeva, V.V.; Lysov, Y.P.; Karpov, V.L.; Karpov, D.S. Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation. Int. J. Mol. Sci. 2020, 21, 8097.

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