title: Proteasome inhibition enhances resistance to DNA damage via upregulation of Rpn4-dependent DNA repair genes.
abstract: 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.
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Department of Chromatin Structure and Functions, Vavilov Str. 32, Moscow 119991, Russia. aleom@yandex.ru
authors: Dmitry S
authors: DS
authors: Karpov
authors: Daria S
authors: DS
authors: Spasskaya
authors: Vera V
authors: VV
authors: Tutyaeva
authors: Alexander S
authors: AS
authors: Mironov
authors: Vadim L
authors: VL
authors: Karpov
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D001383:Azetidinecarboxylic Acid / Q000494:pharmacology; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004271:DNA, Fungal / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D059765:Homologous Recombination; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D009097:Multienzyme Complexes; C490846:RAD23 protein, S cerevisiae; C497197:RAD52 protein, S cerevisiae; C119430:RPN4 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D015112:4-Nitroquinoline-1-oxide; D001383:Azetidinecarboxylic Acid; D008741:Methyl Methanesulfonate; D045647:DNA Glycosylases; C445668:MAG1 protein, S cerevisiae; C083706:PRE1 protein, S cerevisiae; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: 4-nitroquinoline 1-oxide; 4NQO; AZE; DNA damage response; DSB-HR; MMS; Proteasome; RAD52; Rpn4; Yeast; double strand break repair by homologous recombination; l-azetidine-2-carboxylic acid; methyl-4-methanesulfonate