Disease relevance of RAD23

• Purification and cloning of a nucleotide excision repair complex involving the xeroderma pigmentosum group C protein and a human homologue of yeast RAD23 [1].
• Therefore, our findings suggest that Rad23 might induce resistance to methylmercury in yeast cells by suppressing the degradation of proteins that reduce the toxicity of methylmercury via a UBA domain-mediated mechanism [2].

High impact information on RAD23

• In vivo analyses confirmed that Rad23 and the multiubiquitin binding domain of Rpn10 contribute to Sic1 degradation [3].
• The CYC7-H3 deletion encompasses the RAD23 locus, which controls UV sensitivity and the ANP1 locus, which controls osmotic sensitivity [4].
• The carboxy terminus of Rad23 binds to the Rad4 DNA repair protein and creates a link between the DNA repair and proteasome pathways [5].
• Rad23 links DNA repair to the ubiquitin/proteasome pathway [5].
• Cdc48-Ufd2-Rad23: the road less ubiquitinated [6]?

Biological context of RAD23

• The only other known yeast ubiquitin-like protein is encoded by the nucleotide excision repair gene RAD23 (Watkins, J.F.,P. Sung, L. Prakash, and S. Prakash. 1993. Mol. Cell. Bio. 13:7757-7765) [7].
• RAD7 gene of Saccharomyces cerevisiae: transcripts, nucleotide sequence analysis, and functional relationship between the RAD7 and RAD23 gene products [8].
• Cell cycle progression in the triple deletion strain can only be partially rescued by a rad23 allele lacking the c-terminal UBA domain, suggesting that RAD23 requires its c-terminal UBA domain for full function [9].
• RAD23 and DDI1 suppress the temperature and hydroxyurea, but not radiation or nocodazole, sensitivity of pds1-128. rad23 and ddi1 mutants are partially defective in S-phase checkpoint control but are proficient in DNA damage and spindle assembly checkpoints [10].
• Deletion of the UBA domains of Rad23p and Ddi1p renders cells defective in S-phase checkpoint control, implicating UBA domains in checkpoint signaling [10].

Anatomical context of RAD23

• We have used a cell-free system to study the roles of the Rad7, Rad16, and Rad23 proteins in NER [11].
• Multiple-tissue expression profile of the messenger RNA (mRNA) that encodes the RAD23-like protein B also showed that it is highly expressed in the human testis and in ejaculated spermatozoa [12].

Associations of RAD23 with chemical compounds

• Although rad23Delta rpn10Delta displays similar sensitivity to DNA damage as a rad23Delta single mutant, deletion of RAD23 in rpn10Delta significantly increased sensitivity to canavanine, a phenotype associated with an rpn10Delta single mutant [13].
• Purified Rad23 protein was unable to bind to DNA, but stimulated the binding activity of purified Rad4 protein to N-acetyl-2-aminofluorene-damaged DNA [14].
• The Png1-Rad23 complex regulates glycoprotein turnover [15].
• In contrast, cells that overexpressed Rad23 with a defective UBA domain were not resistant to methylmercury and contained control levels of ubiquitinated proteins [2].
• Defective excision of pyrimidine dimers and interstrand DNA crosslinks in rad7 and rad23 mutants of Saccharomyces cerevisiae [16].

Physical interactions of RAD23

• Pth2 bound to the UBL domain of both Rad23 and Dsk2 [17].
• Rad23 contains a ubiquitin-like domain (UbL(R23)) that interacts with catalytically active proteasomes and two ubiquitin (Ub)-associated (UBA) sequences that bind Ub [18].
• Here, we demonstrate that the UBL motif of Rad23 also binds Ufd2, an E4 enzyme essential for ubiquitin chain assembly onto its substrates [19].
• More recent studies in yeast indicate that Png1p can bind to the 26S proteasome through its interaction with the DNA repair protein Rad23p [20].

Regulatory relationships of RAD23

• As Rad23 also controls Rad4 levels, these results suggest a complex system for globally regulating repair activity in vivo by controlling turnover of Rad4 [21].
• Yeast DNA repair protein RAD23 promotes complex formation between transcription factor TFIIH and DNA damage recognition factor RAD14 [22].
• We determined that yeast and human Rad23 inhibited multi-ubiquitin (Ub) chain formation and the degradation of proteolytic substrates [23].

Other interactions of RAD23

• Although DSK2 is not essential, a strain deleted for both DSK2 and RAD23 is temperature sensitive for growth due to a block in SPB duplication [7].
• Alternatively, an interaction between the RAD7 and RAD23 proteins could also account for these observations [8].
• Therefore, Rad23p and Ddi1p participate in a subset of Pds1p-dependent cell cycle controls [10].
• Here we show that the proteasome directly recognizes ubiquitin chains through a specific subunit, Rpn10, and also recognizes chains indirectly through Rad23, a reversibly bound proteasome cofactor [24].
• We show that UMP1 is not epistatic to RAD23 and RAD2, which are involved in the nucleotide excision repair (NER) pathway [25].

Analytical, diagnostic and therapeutic context of RAD23

• The interaction between PNGase and Rad23 was studied using surface plasmon resonance revealing an equilibrium binding constant of approximately 2.5 microM [26].
• Yeast peptide: N-glycanase (PNGase) is involved in the proteasomal degradation of misfolded glycoproteins where it interacts with the DNA repair protein Rad23 as first detected in a yeast two-hybrid assay and subsequently confirmed by biochemical in vivo analyses [26].

References