| Structural highlights
Disease
XPC_HUMAN Defects in XPC are a cause of xeroderma pigmentosum complementation group C (XP-C) [MIM:278720; also known as xeroderma pigmentosum III (XP3). XP-C is a rare human autosomal recessive disease characterized by solar sensitivity, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities.[1] [2] [3] [4] [5]
Function
XPC_HUMAN Involved in global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex. Has only a low DNA repair activity by itself which is stimulated by RAD23B and RAD23A. Has a preference to bind DNA containing a short single-stranded segment but not to damaged oligonucleotides. This feature is proposed to be related to a dynamic sensor function: XPC can rapidly screen duplex DNA for non-hydrogen-bonded bases by forming a transient nucleoprotein intermediate complex which matures into a stable recognition complex through an intrinsic single-stranded DNA-binding activity.[6] [7] [8] [9] [10] [11] [12] [13] [14] [15] 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.[16] [17] [18] [19] [20] [21] [22] [23] [24] [25]
Publication Abstract from PubMed
In global genome repair (GGR), XPC detects damaged nucleotides and recruits TFIIH complex. The small acidic region of XPC binds to the pleckstrin homology (PH) domain of TFIIH subunit p62; however, the recognition mechanism remains elusive. Here, we use nuclear magnetic resonance to present the tertiary structure of XPC bound to the PH domain. The XPC acidic region forms a long string stabilized by insertion of Trp133 and Val136 into two separate hollows of the PH domain, coupled with extensive electrostatic contacts. Analysis of several XPC mutants revealed that particularly Trp133 is essential for binding to the PH domain. In cell lines stably expressing mutant XPC, alanine substitution at Trp133 or Trp133/Val136 compromised UV resistance, recruitment of TFIIH to DNA damage, and removal of UV-induced photoproducts from genomic DNA. These findings show how TFIIH complex is recruited by XPC to damaged DNA, advancing our understanding of the early stage of GGR.
Structural Insight into the Mechanism of TFIIH Recognition by the Acidic String of the Nucleotide Excision Repair Factor XPC.,Okuda M, Kinoshita M, Kakumu E, Sugasawa K, Nishimura Y Structure. 2015 Aug 10. pii: S0969-2126(15)00290-7. doi:, 10.1016/j.str.2015.07.009. PMID:26278177[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Camenisch U, Trautlein D, Clement FC, Fei J, Leitenstorfer A, Ferrando-May E, Naegeli H. Two-stage dynamic DNA quality check by xeroderma pigmentosum group C protein. EMBO J. 2009 Aug 19;28(16):2387-99. doi: 10.1038/emboj.2009.187. Epub 2009 Jul, 16. PMID:19609301 doi:10.1038/emboj.2009.187
- ↑ Yasuda G, Nishi R, Watanabe E, Mori T, Iwai S, Orioli D, Stefanini M, Hanaoka F, Sugasawa K. In vivo destabilization and functional defects of the xeroderma pigmentosum C protein caused by a pathogenic missense mutation. Mol Cell Biol. 2007 Oct;27(19):6606-14. Epub 2007 Aug 6. PMID:17682058 doi:10.1128/MCB.02166-06
- ↑ Maillard O, Solyom S, Naegeli H. An aromatic sensor with aversion to damaged strands confers versatility to DNA repair. PLoS Biol. 2007 Apr;5(4):e79. PMID:17355181 doi:10.1371/journal.pbio.0050079
- ↑ Li L, Bales ES, Peterson CA, Legerski RJ. Characterization of molecular defects in xeroderma pigmentosum group C. Nat Genet. 1993 Dec;5(4):413-7. PMID:8298653 doi:http://dx.doi.org/10.1038/ng1293-413
- ↑ Chavanne F, Broughton BC, Pietra D, Nardo T, Browitt A, Lehmann AR, Stefanini M. Mutations in the XPC gene in families with xeroderma pigmentosum and consequences at the cell, protein, and transcript levels. Cancer Res. 2000 Apr 1;60(7):1974-82. PMID:10766188
- ↑ 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
- ↑ Yokoi M, Masutani C, Maekawa T, Sugasawa K, Ohkuma Y, Hanaoka F. The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of transcription factor IIH to damaged DNA. J Biol Chem. 2000 Mar 31;275(13):9870-5. PMID:10734143
- ↑ 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
- ↑ Camenisch U, Trautlein D, Clement FC, Fei J, Leitenstorfer A, Ferrando-May E, Naegeli H. Two-stage dynamic DNA quality check by xeroderma pigmentosum group C protein. EMBO J. 2009 Aug 19;28(16):2387-99. doi: 10.1038/emboj.2009.187. Epub 2009 Jul, 16. PMID:19609301 doi:10.1038/emboj.2009.187
- ↑ 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
- ↑ Clement FC, Kaczmarek N, Mathieu N, Tomas M, Leitenstorfer A, Ferrando-May E, Naegeli H. Dissection of the xeroderma pigmentosum group C protein function by site-directed mutagenesis. Antioxid Redox Signal. 2011 Jun 15;14(12):2479-90. doi: 10.1089/ars.2010.3399., Epub 2010 Oct 7. PMID:20649465 doi:10.1089/ars.2010.3399
- ↑ 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
- ↑ 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
- ↑ Yokoi M, Masutani C, Maekawa T, Sugasawa K, Ohkuma Y, Hanaoka F. The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of transcription factor IIH to damaged DNA. J Biol Chem. 2000 Mar 31;275(13):9870-5. PMID:10734143
- ↑ 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
- ↑ Camenisch U, Trautlein D, Clement FC, Fei J, Leitenstorfer A, Ferrando-May E, Naegeli H. Two-stage dynamic DNA quality check by xeroderma pigmentosum group C protein. EMBO J. 2009 Aug 19;28(16):2387-99. doi: 10.1038/emboj.2009.187. Epub 2009 Jul, 16. PMID:19609301 doi:10.1038/emboj.2009.187
- ↑ 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
- ↑ Clement FC, Kaczmarek N, Mathieu N, Tomas M, Leitenstorfer A, Ferrando-May E, Naegeli H. Dissection of the xeroderma pigmentosum group C protein function by site-directed mutagenesis. Antioxid Redox Signal. 2011 Jun 15;14(12):2479-90. doi: 10.1089/ars.2010.3399., Epub 2010 Oct 7. PMID:20649465 doi:10.1089/ars.2010.3399
- ↑ 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
- ↑ Okuda M, Kinoshita M, Kakumu E, Sugasawa K, Nishimura Y. Structural Insight into the Mechanism of TFIIH Recognition by the Acidic String of the Nucleotide Excision Repair Factor XPC. Structure. 2015 Aug 10. pii: S0969-2126(15)00290-7. doi:, 10.1016/j.str.2015.07.009. PMID:26278177 doi:http://dx.doi.org/10.1016/j.str.2015.07.009
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