| Structural highlights
Function
RD23B_HUMAN Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Binds to polyubiquitin chains. Proposed to be capable to bind simultaneously to the 26S proteasome and to polyubiquitinated substrates and to deliver ubiquitinated proteins to the proteasome. May play a role in endoplasmic reticulum-associated degradation (ERAD) of misfolded glycoproteins by association with PNGase and delivering deglycosylated proteins to the proteasome.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Involved in global genome nucleotide excision repair (GG-NER) by acting as component of the XPC complex. Cooperatively with CETN2 appears to stabilize XPC. May protect XPC from proteasomal degradation.[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair. In vitro, the XPC:RAD23B dimer is sufficient to initiate NER; it preferentially binds to cisplatin and UV-damaged double-stranded DNA and also binds to a variety of chemically and structurally diverse DNA adducts. XPC:RAD23B contacts DNA both 5' and 3' of a cisplatin lesion with a preference for the 5' side. XPC:RAD23B induces a bend in DNA upon binding. XPC:RAD23B stimulates the activity of DNA glycosylases TDG and SMUG1.[23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]
Publication Abstract from PubMed
Increasing brain complexity is a major step in the evolution of species. Here, we show that, in the transition from amphibians to reptiles, the DNA repair protein RAD23B acquires a metalloadaptor function that allows it to serve as a central hub for both metabolism and protection of genomic integrity. More specifically, RAD23B gains an allosteric H274/H323 copper-binding site to enable the transfer of copper from the universal copper transporter 1 (CTR1) uptake protein to all known copper metallochaperone pathways, while simultaneously making its canonical functions in DNA repair copper dependent. This layer of nutrient regulation allows organisms to withstand elevated levels of potentially toxic copper while augmenting metabolism in cells with high energetic needs across both physiology and disease, including neurons in the locus coeruleus, a key brain structure that regulates sleep, and cancer cells.
RAD23B acquires a copper metalloadaptor function in amphibian-to-reptile evolution to increase metabolism and regulate genomic integrity.,Xiao T, He D, Liu D, Jia S, Chen Q, Silverman D, Maitra N, Huang AY, Pezacki A, Nguyen TT, Rao G, Tillage R, Deng K, Weinshenker D, Britt RD, Kelly MJS, Dan Y, Chang CJ Mol Cell. 2025 Sep 18;85(18):3443-3459.e11. doi: 10.1016/j.molcel.2025.08.024. PMID:40972527[34]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sugasawa K, Ng JM, Masutani C, Maekawa T, Uchida A, van der Spek PJ, Eker AP, Rademakers S, Visser C, Aboussekhra A, Wood RD, Hanaoka F, Bootsma D, Hoeijmakers JH. Two human homologs of Rad23 are functionally interchangeable in complex formation and stimulation of XPC repair activity. Mol Cell Biol. 1997 Dec;17(12):6924-31. PMID:9372924
- ↑ Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH. Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol Cell. 1998 Aug;2(2):223-32. PMID:9734359
- ↑ Batty D, Rapic'-Otrin V, Levine AS, Wood RD. Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites. J Mol Biol. 2000 Jul 7;300(2):275-90. PMID:10873465 doi:10.1006/jmbi.2000.3857
- ↑ Sugasawa K, Shimizu Y, Iwai S, Hanaoka F. A molecular mechanism for DNA damage recognition by the xeroderma pigmentosum group C protein complex. DNA Repair (Amst). 2002 Jan 22;1(1):95-107. PMID:12509299
- ↑ Janicijevic A, Sugasawa K, Shimizu Y, Hanaoka F, Wijgers N, Djurica M, Hoeijmakers JH, Wyman C. DNA bending by the human damage recognition complex XPC-HR23B. DNA Repair (Amst). 2003 Mar 1;2(3):325-36. PMID:12547395
- ↑ Ng JM, Vermeulen W, van der Horst GT, Bergink S, Sugasawa K, Vrieling H, Hoeijmakers JH. A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein. Genes Dev. 2003 Jul 1;17(13):1630-45. Epub 2003 Jun 18. PMID:12815074 doi:http://dx.doi.org/10.1101/gad.260003
- ↑ Li X, Demartino GN. Variably modulated gating of the 26S proteasome by ATP and polyubiquitin. Biochem J. 2009 Jul 15;421(3):397-404. doi: 10.1042/BJ20090528. PMID:19435460 doi:http://dx.doi.org/10.1042/BJ20090528
- ↑ Sugasawa K, Akagi J, Nishi R, Iwai S, Hanaoka F. Two-step recognition of DNA damage for mammalian nucleotide excision repair: Directional binding of the XPC complex and DNA strand scanning. Mol Cell. 2009 Nov 25;36(4):642-53. doi: 10.1016/j.molcel.2009.09.035. PMID:19941824 doi:10.1016/j.molcel.2009.09.035
- ↑ Neher TM, Rechkunova NI, Lavrik OI, Turchi JJ. Photo-cross-linking of XPC-Rad23B to cisplatin-damaged DNA reveals contacts with both strands of the DNA duplex and spans the DNA adduct. Biochemistry. 2010 Feb 2;49(4):669-78. doi: 10.1021/bi901575h. PMID:20028083 doi:10.1021/bi901575h
- ↑ Shimizu Y, Uchimura Y, Dohmae N, Saitoh H, Hanaoka F, Sugasawa K. Stimulation of DNA Glycosylase Activities by XPC Protein Complex: Roles of Protein-Protein Interactions. J Nucleic Acids. 2010 Jul 25;2010. pii: 805698. doi: 10.4061/2010/805698. PMID:20798892 doi:10.4061/2010/805698
- ↑ Kim B, Ryu KS, Kim HJ, Cho SJ, Choi BS. Solution structure and backbone dynamics of the XPC-binding domain of the human DNA repair protein hHR23B. FEBS J. 2005 May;272(10):2467-76. PMID:15885096 doi:10.1111/j.1742-4658.2005.04667.x
- ↑ Sugasawa K, Ng JM, Masutani C, Maekawa T, Uchida A, van der Spek PJ, Eker AP, Rademakers S, Visser C, Aboussekhra A, Wood RD, Hanaoka F, Bootsma D, Hoeijmakers JH. Two human homologs of Rad23 are functionally interchangeable in complex formation and stimulation of XPC repair activity. Mol Cell Biol. 1997 Dec;17(12):6924-31. PMID:9372924
- ↑ Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH. Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol Cell. 1998 Aug;2(2):223-32. PMID:9734359
- ↑ Batty D, Rapic'-Otrin V, Levine AS, Wood RD. Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites. J Mol Biol. 2000 Jul 7;300(2):275-90. PMID:10873465 doi:10.1006/jmbi.2000.3857
- ↑ Sugasawa K, Shimizu Y, Iwai S, Hanaoka F. A molecular mechanism for DNA damage recognition by the xeroderma pigmentosum group C protein complex. DNA Repair (Amst). 2002 Jan 22;1(1):95-107. PMID:12509299
- ↑ Janicijevic A, Sugasawa K, Shimizu Y, Hanaoka F, Wijgers N, Djurica M, Hoeijmakers JH, Wyman C. DNA bending by the human damage recognition complex XPC-HR23B. DNA Repair (Amst). 2003 Mar 1;2(3):325-36. PMID:12547395
- ↑ Ng JM, Vermeulen W, van der Horst GT, Bergink S, Sugasawa K, Vrieling H, Hoeijmakers JH. A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein. Genes Dev. 2003 Jul 1;17(13):1630-45. Epub 2003 Jun 18. PMID:12815074 doi:http://dx.doi.org/10.1101/gad.260003
- ↑ Li X, Demartino GN. Variably modulated gating of the 26S proteasome by ATP and polyubiquitin. Biochem J. 2009 Jul 15;421(3):397-404. doi: 10.1042/BJ20090528. PMID:19435460 doi:http://dx.doi.org/10.1042/BJ20090528
- ↑ Sugasawa K, Akagi J, Nishi R, Iwai S, Hanaoka F. Two-step recognition of DNA damage for mammalian nucleotide excision repair: Directional binding of the XPC complex and DNA strand scanning. Mol Cell. 2009 Nov 25;36(4):642-53. doi: 10.1016/j.molcel.2009.09.035. PMID:19941824 doi:10.1016/j.molcel.2009.09.035
- ↑ Neher TM, Rechkunova NI, Lavrik OI, Turchi JJ. Photo-cross-linking of XPC-Rad23B to cisplatin-damaged DNA reveals contacts with both strands of the DNA duplex and spans the DNA adduct. Biochemistry. 2010 Feb 2;49(4):669-78. doi: 10.1021/bi901575h. PMID:20028083 doi:10.1021/bi901575h
- ↑ Shimizu Y, Uchimura Y, Dohmae N, Saitoh H, Hanaoka F, Sugasawa K. Stimulation of DNA Glycosylase Activities by XPC Protein Complex: Roles of Protein-Protein Interactions. J Nucleic Acids. 2010 Jul 25;2010. pii: 805698. doi: 10.4061/2010/805698. PMID:20798892 doi:10.4061/2010/805698
- ↑ Kim B, Ryu KS, Kim HJ, Cho SJ, Choi BS. Solution structure and backbone dynamics of the XPC-binding domain of the human DNA repair protein hHR23B. FEBS J. 2005 May;272(10):2467-76. PMID:15885096 doi:10.1111/j.1742-4658.2005.04667.x
- ↑ Sugasawa K, Ng JM, Masutani C, Maekawa T, Uchida A, van der Spek PJ, Eker AP, Rademakers S, Visser C, Aboussekhra A, Wood RD, Hanaoka F, Bootsma D, Hoeijmakers JH. Two human homologs of Rad23 are functionally interchangeable in complex formation and stimulation of XPC repair activity. Mol Cell Biol. 1997 Dec;17(12):6924-31. PMID:9372924
- ↑ Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH. Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol Cell. 1998 Aug;2(2):223-32. PMID:9734359
- ↑ Batty D, Rapic'-Otrin V, Levine AS, Wood RD. Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites. J Mol Biol. 2000 Jul 7;300(2):275-90. PMID:10873465 doi:10.1006/jmbi.2000.3857
- ↑ Sugasawa K, Shimizu Y, Iwai S, Hanaoka F. A molecular mechanism for DNA damage recognition by the xeroderma pigmentosum group C protein complex. DNA Repair (Amst). 2002 Jan 22;1(1):95-107. PMID:12509299
- ↑ Janicijevic A, Sugasawa K, Shimizu Y, Hanaoka F, Wijgers N, Djurica M, Hoeijmakers JH, Wyman C. DNA bending by the human damage recognition complex XPC-HR23B. DNA Repair (Amst). 2003 Mar 1;2(3):325-36. PMID:12547395
- ↑ Ng JM, Vermeulen W, van der Horst GT, Bergink S, Sugasawa K, Vrieling H, Hoeijmakers JH. A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein. Genes Dev. 2003 Jul 1;17(13):1630-45. Epub 2003 Jun 18. PMID:12815074 doi:http://dx.doi.org/10.1101/gad.260003
- ↑ Li X, Demartino GN. Variably modulated gating of the 26S proteasome by ATP and polyubiquitin. Biochem J. 2009 Jul 15;421(3):397-404. doi: 10.1042/BJ20090528. PMID:19435460 doi:http://dx.doi.org/10.1042/BJ20090528
- ↑ Sugasawa K, Akagi J, Nishi R, Iwai S, Hanaoka F. Two-step recognition of DNA damage for mammalian nucleotide excision repair: Directional binding of the XPC complex and DNA strand scanning. Mol Cell. 2009 Nov 25;36(4):642-53. doi: 10.1016/j.molcel.2009.09.035. PMID:19941824 doi:10.1016/j.molcel.2009.09.035
- ↑ Neher TM, Rechkunova NI, Lavrik OI, Turchi JJ. Photo-cross-linking of XPC-Rad23B to cisplatin-damaged DNA reveals contacts with both strands of the DNA duplex and spans the DNA adduct. Biochemistry. 2010 Feb 2;49(4):669-78. doi: 10.1021/bi901575h. PMID:20028083 doi:10.1021/bi901575h
- ↑ Shimizu Y, Uchimura Y, Dohmae N, Saitoh H, Hanaoka F, Sugasawa K. Stimulation of DNA Glycosylase Activities by XPC Protein Complex: Roles of Protein-Protein Interactions. J Nucleic Acids. 2010 Jul 25;2010. pii: 805698. doi: 10.4061/2010/805698. PMID:20798892 doi:10.4061/2010/805698
- ↑ Kim B, Ryu KS, Kim HJ, Cho SJ, Choi BS. Solution structure and backbone dynamics of the XPC-binding domain of the human DNA repair protein hHR23B. FEBS J. 2005 May;272(10):2467-76. PMID:15885096 doi:10.1111/j.1742-4658.2005.04667.x
- ↑ Xiao T, He D, Liu D, Jia S, Chen Q, Silverman D, Maitra N, Huang AY, Pezacki A, Nguyen TT, Rao G, Tillage R, Deng K, Weinshenker D, Britt RD, Kelly MJS, Dan Y, Chang CJ. RAD23B acquires a copper metalloadaptor function in amphibian-to-reptile evolution to increase metabolism and regulate genomic integrity. Mol Cell. 2025 Sep 18;85(18):3443-3459.e11. PMID:40972527 doi:10.1016/j.molcel.2025.08.024
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