title: A role for Rad23 proteins in 26S proteasome-dependent protein degradation?
abstract: Treatment of cells with genotoxic agents affects protein degradation in both positive and negative ways. Exposure of S. cerevisiae to the alkylating agent MMS resulted in activation of genes that are involved in ubiquitin- and 26S proteasome-dependent protein degradation. This process partially overlaps with the activation of the ER-associated protein degradation pathway. The DNA repair protein Rad23p and its mammalian homologues have been shown to inhibit degradation of specific substrates in response to DNA damage. Particularly the recently identified inhibition of degradation by mouse Rad23 protein (mHR23) of the associated nucleotide excision repair protein XPC was shown to stimulate DNA repair.Recently, it was shown that Rad23p and the mouse homologue mHR23B also associate with Png1p, a deglycosylation enzyme. Png1p-mediated deglycosylation plays a role in ER-associated protein degradation after accumulation of malfolded proteins in the endoplasmic reticulum. Thus, if stabilization of proteins that are associated with the C-terminus of Rad23p is a general phenomenon, then Rad23 might be implicated in the stimulation of ER-associated protein degradation as well. Interestingly, the recently identified HHR23-like protein Mif1 is also thought to play a role in ER-associated protein degradation. The MIF1 gene is strongly activated in response to ER-stress. Mif1 contains a ubiquitin-like domain which is most probably involved in binding to S5a, a subunit of the 19S regulatory complex of the 26S proteasome. On the basis of its localization in the ER-membrane, it is hypothesized that Mif1 could play a role in the translocation of the 26S proteasome towards the ER-membrane, thereby enhancing ER-associated protein degradation.
authors.affiliation: MGC Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Centre, P.O. Box 9503, 2300 RA Leiden, The Netherlands. t.van_laar@lumc.nl
authors.forename: Theo
authors.initials: T
authors.lastname: van Laar
authors.forename: Alex J
authors.initials: AJ
authors.lastname: van der Eb
authors.forename: Carrol
authors.initials: C
authors.lastname: Terleth
mesh_terms: D000818:Animals; D001426:Bacterial Proteins; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D013381:Subtilisins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; C490846:RAD23 protein, S cerevisiae; C119430:RPN4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D025821:Polyubiquitin; C086985:RAD23A protein, human; D008741:Methyl Methanesulfonate; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D010447:Peptide Hydrolases; C430046:HreP protein, Yersinia enterocolitica; D013381:Subtilisins; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D045643:DNA Repair Enzymes