Disease relevance of RAD23A

• We also determined that hHR23A and hHR23B could be co-purified with unique proteolytic and stress-responsive factors from human breast cancer tissues, indicating that they have unique functions in vivo [1].
• Analysis of apoptosis induced by HIV-1 Vpr and examination of the possible role of the hHR23A protein [2].
• Yeast two-hybrid selection of proteins interacting with human immunodeficiency virus type 1 Vpr identified HHR23A, a human homologue of the yeast DNA repair protein RAD23, as a specific interactor [3].
• The two human homologs of Rad23, hHR23A and B, are functionally redundant in NER and interact with xeroderma pigmentosum complementation group C (XPC) protein [4].

High impact information on RAD23A

• Here, we use NMR to unveil the structural basis of selective recognition of Lys48-linked di- and tetraubiquitin chains by the UBA2 domain of hHR23A [5].
• HHR23A, a protein implicated in nucleotide excision repair, belongs to a class of proteins containing both a ubiquitin-like (Ubl) domain and one or more ubiquitin-associated (UBA) domains, suggesting a role in the ubiquitin-proteasome pathway as well [6].
• However, in 293 cells HHR23A is recruited to intranuclear inclusions formed by the mutant ataxin-3 through its interaction with ataxin-3 [7].
• In this report, we show that the hHR23A and -B also interact with the MPG protein and can serve as accessory proteins for DNA damage recognition in base excision repair [8].
• HHR23A binds E6AP and is ubiquitinated in vitro in an E6AP-dependent manner [9].

Biological context of RAD23A

• In these hHR23A(KD) cells, the XPC gene was not normally induced by UVC irradiation, indicating that the hHR23A protein is involved in NER through regulation of the DNA damage recognition protein XPC [10].
• In this study, the potential function of the hHR23A protein was investigated using RNA interference techniques [10].
• Evidence for distinct functions for human DNA repair factors hHR23A and hHR23B [1].
• The HHR23A gene was assigned to chromosome 19p13 [11].
• Although the precise role of HHR23 proteins in DNA repair and cell cycle progression remains to be elucidated, our data suggest that E6AP-mediated ubiquitination of HHR23A may have important implications in DNA repair and cell cycle progression [9].

Anatomical context of RAD23A

• Visualization of HHR23A and Vpr by indirect immunofluorescence and confocal microscopy indicates that the two proteins colocalize at or about the nuclear membrane [12].

Associations of RAD23A with chemical compounds

• Threonine-79 contributed to the weak proteasome-binding property of hHR23A, and its conversion to proline (T79P), which is the residue present in hHR23B, increased proteasome interaction [1].
• We present evidence that the UBL domain of HHR23A negatively regulates polyubiquitin/UBA interactions and identify leucine 8 of ubiquitin as an important determinant of chain recognition [13].

Physical interactions of RAD23A

• Consistent with this hypothesis, an MDM2 mutant that demonstrated increased binding in vivo to hHR23A was able to ubiquitinate, but not degrade p53 [14].
• Structure of the XPC binding domain of hHR23A reveals hydrophobic patches for protein interaction [4].
• However, the interaction is dissimilar to the molecular models proposed for the hHR23A UBA domains bound to either monoubiquitin or Lys48-linked diubiquitin [15].

Other interactions of RAD23A

• The hHR23A knock-down (KD) construct diminished the RNA level of hHR23A protein by approximately 60%, and it did not interfere with expression of the hHR23B gene [10].
• Moreover, the defective phenotype of this MDM2 mutant was rescued by siRNA knockdown of hHR23A [14].
• Although HHR23A is a stable protein in non-synchronized cells, its levels are regulated in a cell cycle-dependent manner, with specific degradation occurring during S phase [9].

Analytical, diagnostic and therapeutic context of RAD23A

• Consistent with a function in repair or DNA/chromatin metabolism, immunofluorescence studies show all XPC, HHR23B and (the free) HHR23A to reside in the nucleus [16].
• Here, we report the results of a quantitative study of the interaction of K48-linked polyubiquitin chains with UBA domains of the DNA repair/proteolysis protein HHR23A, using surface plasmon resonance and other approaches [13].

References