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

•Mutation of PACE in the PRE1 promoter decreases proteasome activity.•Proteasome deregulation increases resistance to DNA damage.•Upon proteasome inhibition, Rpn4 is stabilised and upregulates DNA repair genes.•The proteasome mutant strain displays enhanced activity of DSB repair. The 26S proteasome...

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Bibliographic Details
Published in:FEBS letters 2013-09, Vol.587 (18), p.3108-3114
Main Authors: Karpov, Dmitry S., Spasskaya, Daria S., Tutyaeva, Vera V., Mironov, Alexander S., Karpov, Vadim L.
Format: Article
Language:English
Subjects:
4-nitroquinoline 1-oxide
4-Nitroquinoline-1-oxide - pharmacology
4NQO
AZE
Azetidinecarboxylic Acid - pharmacology
DNA Damage
DNA damage response
DNA Glycosylases - genetics
DNA Glycosylases - metabolism
DNA Repair - genetics
DNA, Fungal - drug effects
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
double strand break repair by homologous recombination
DSB-HR
Gene Expression Regulation, Fungal - drug effects
Homologous Recombination
l-azetidine-2-carboxylic acid
Methyl Methanesulfonate - pharmacology
methyl-4-methanesulfonate
MMS
Multienzyme Complexes - deficiency
Multienzyme Complexes - genetics
Proteasome
Proteasome Endopeptidase Complex - drug effects
Proteasome Endopeptidase Complex - genetics
Proteasome Endopeptidase Complex - metabolism
RAD52
Rad52 DNA Repair and Recombination Protein - genetics
Rad52 DNA Repair and Recombination Protein - metabolism
Rpn4
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic - drug effects
Yeast
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Summary:•Mutation of PACE in the PRE1 promoter decreases proteasome activity.•Proteasome deregulation increases resistance to DNA damage.•Upon proteasome inhibition, Rpn4 is stabilised and upregulates DNA repair genes.•The proteasome mutant strain displays enhanced activity of DSB repair. The 26S proteasome is an ATP-dependent multi-subunit protease complex and the major regulator of intracellular protein turnover and quality control. However, its role in the DNA damage response is controversial. We addressed this question in yeast by disrupting the transcriptional regulation of the PRE1 proteasomal gene. The mutant strain has decreased proteasome activity and is hyper-resistant to various DNA-damaging agents. We found that Rpn4-target genes MAG1, RAD23, and RAD52 are overexpressed in this strain due to Rpn4 stabilisation. These genes represent three different pathways of base excision, nucleotide excision and double strand break repair by homologous recombination (DSB-HR). Consistently, the proteasome mutant displays increased DSB-HR activity. Our data imply that the proteasome may have a negative role in DNA damage response.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2013.08.007