Alternative titles; symbols
HGNC Approved Gene Symbol: RAD23A
Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38): 19:12,945,862-12,953,642 (from NCBI)
RAD23A and RAD23B (600062), the human orthologs of yeast rad23, play distinct roles in nucleotide excision DNA repair (NER) and in the ubiquitin-proteasome system (UPS). NER is a genome maintenance pathway responsible for repair of bulky DNA lesions, and UPS performs protein degradation in diverse cellular processes, including DNA repair (summary by Bergink et al., 2013).
Masutani et al. (1994) reported the purification to homogeneity and subsequent cDNA cloning from HeLa cells of a repair complex by in vitro complementation of the xeroderma pigmentosum group C (278720) defect in a cell-free repair system containing UV-damaged SV40 minichromosomes. The complex had a high affinity for ssDNA and consisted of 2 tightly associated proteins of 125 and 58 kD. The 125-kD subunit represented the previously reported XPC gene (613208) product, which represents the human homolog of the NER gene RAD4 of Saccharomyces cerevisiae. The 58-kD species turned out to be a human homolog of yeast RAD23. Unexpectedly, a second human counterpart of RAD23 was identified. The 2 genes, which Masutani et al. (1994) referred to as HHR23A (RAD23A) and HHR23B (RAD23B), contain 363 and 409 amino acids, respectively, and both have an N-terminal domain that shares significant similarity with ubiquitin (UBB; 191339) and various ubiquitin fusion proteins. Both RAD23A and RAD23B were expressed in the same cells. In the XPC purification scheme, however, only the RAD23B protein was found in a complex with p125/XPC.
In mouse, van der Spek et al. (1996) cloned the homologs of RAD23A and RAD23B. Detailed sequence comparisons permitted deductions concerning the structure of all RAD23 homologs. Northern blot analysis revealed constitutive expression of both RAD23 genes in all tissues examined. Elevated RNA expression of both genes was observed in testis.
Using fluorescence in situ hybridization (FISH), van der Spek et al. (1994) demonstrated that the RAD23A gene is located on 19p13.2.
By FISH, van der Spek et al. (1996) assigned the Rad23a gene to mouse chromosome 8C3 and the Rad23b gene to mouse chromosome 4B3.
Masutani et al. (1994) commented that no human mutant defective in RAD23A had been identified. They suggested that the nature of the defect in xeroderma pigmentosum group C implies that the XPC-RAD23B complex exerts a unique function in the genome-overall repair pathway that is important for prevention of skin cancer.
Van der Spek et al. (1996) found that although the RAD23 equivalents are well conserved during evolution, the mammalian genes do not express the UV-inducible phenotype of their yeast counterpart. The authors stated that this discovery may point to a fundamental difference between the UV responses of yeast and human.
Machado-Joseph disease (MJD; 109150) is an autosomal dominant neurodegenerative disorder caused by an expansion of the polyglutamine tract near the C terminus of the MJD1 gene product, ataxin-3. The mutant ataxin-3 forms intranuclear inclusions in cultured cells as well as in diseased human brain and also causes cell death in transfected cells. Using a 2-hybrid system, Wang et al. (2000) found that ataxin-3 interacts with 2 human homologs of the yeast DNA repair protein RAD23, RAD23A and RAD23B. Both normal and mutant ataxin-3 proteins interact with the ubiquitin-like domain at the N terminus of the RAD23 proteins, which is a motif important for nucleotide excision repair. However, in human embryonic kidney cells RAD23 is recruited to intranuclear inclusions formed by the mutant ataxin-3 through its interaction with ataxin-3. The authors suggested that this interaction may be associated with the normal function of ataxin-3, and that some functional abnormality of the RAD23 proteins may exist in MJD.
Chen and Madura (2006) stated that HHR23A and HHR23B have redundant roles in DNA repair. However, they presented evidence that the 2 proteins have distinct functions in protein degradation. Full-length RAD23B and its isolated UBB-like domain bound yeast and human proteasome subunits with higher affinity than RAD23A. RAD23B was also associated with higher proteasome-dependent chymotryptic activity than RAD23A. Protein pull-down, mass spectrometry, and Western blot analyses revealed that the 2 proteins bound overlapping but distinct sets of multiubiquitinated proteins, proteasome subunits, stress response proteins, and elongation factors. Mutation analysis revealed that thr79 in RAD23A inhibited proteasome binding, and substitution of thr79 with pro, which is found in RAD23B, increased the ability of RAD23A to bind proteasome subunits. The substitution had no effect on the binding of RAD23A to multiubiquitinated proteins. Mutation analysis further revealed that lys8 of RAD23A and lys6 of RAD23B were critical for binding to proteasome subunits, but not to ataxin-3 (ATXN3; 607047). Chen and Madura (2006) concluded that RAD23A and RAD23B are likely to perform distinct cellular functions that require the proteasome.
Bergink, S., Theil, A. F., Toussaint, W., De Cuyper, I. M., Kulu, D. I., Clapes, T., van der Linden, R., Demmers, J. A., Mul, E. P., van Alphen, F. P., Marteijn, J. A., van Gent, T., Maas, A., Robin, C., Philipsen, S., Vermeulen, W., Mitchell, J. R., Gutierrez, L. Erythropoietic defect associated with reduced cell proliferation in mice lacking the 26S proteasome shuttling factor Rad23b. Molec. Cell. Biol. 33: 3879-3892, 2013. [PubMed: 23897431] [Full Text: https://doi.org/10.1128/MCB.05772-11]
Chen, L., Madura, K. Evidence for distinct functions for human DNA repair factors hHR23A and hHR23B. FEBS Lett. 580: 3401-3408, 2006. [PubMed: 16712842] [Full Text: https://doi.org/10.1016/j.febslet.2006.05.012]
Masutani, C., Sugasawa, K., Yanagisawa, J., Sonoyama, T., Ui, M., Enomoto, T., Takio, K., Tanaka, K., van der Spek, P. J., Bootsma, D., Hoeijmakers, J. H. J., Hanaoka, F. Purification and cloning of a nucleotide excision repair complex involving the xeroderma pigmentosum group C protein and a human homologue of yeast RAD23. EMBO J. 13: 1831-1843, 1994. [PubMed: 8168482] [Full Text: https://doi.org/10.1002/j.1460-2075.1994.tb06452.x]
van der Spek, P. J., Smit, E. M. E., Beverloo, H. B., Sugasawa, K., Masutani, C., Hanaoka, F., Hoeijmakers, J. H. J., Hagemeijer, A. Chromosomal localization of three repair genes: the xeroderma pigmentosum group C gene and two human homologs of yeast RAD23. Genomics 23: 651-658, 1994. [PubMed: 7851894] [Full Text: https://doi.org/10.1006/geno.1994.1554]
van der Spek, P. J., Visser, C. E., Hanaoka, F., Smit, B., Hagemeijer, A., Bootsma, D., Hoeijmakers, J. H. J. Cloning, comparative mapping, and RNA expression of the mouse homologues of the Saccharomyces cerevisiae nucleotide excision repair gene RAD23. Genomics 31: 20-27, 1996. [PubMed: 8808275] [Full Text: https://doi.org/10.1006/geno.1996.0004]
Wang, G., Sawai, N., Kotliarova, S., Kanazawa, I., Nukina, N. Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. Hum. Molec. Genet. 9: 1795-1803, 2000. [PubMed: 10915768] [Full Text: https://doi.org/10.1093/hmg/9.12.1795]