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.

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.