XPC:RAD23:CETN2 and UV-DDB bind distorted dsDNA site

Stable Identifier
Reaction [binding]
Homo sapiens
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XPC, in complex with RAD23B or RAD23A and CETN2, employs a two-stage process to recognize a distorted DNA helix. In the first stage, XPC rapidly probes dsDNA, which is promoted by a DNA repulsive action of a negatively charged beta-turn extension of XPC, located in the vicinity of the XPC DNA-binding domain. In the second stage, the DNA binding domain, consisting of two beta hairpins, binds non-hydrogen bonded bases in dsDNA (Camenisch et al. 2009). Rad4, the yeast ortholog of XPC, recognizes lesions that thermodynamically disrupt normal Watson-Crick base pairing. Rad4 inserts a beta-hairpin through the DNA duplex, causing damaged base pairs to flip out of the double helix. Rad4 associates with the undamaged strand, whereas the DNA strand that contains damaged nucleotides becomes distorted (Min and Pavletich 2007).

Binding of the XPC:RAD23:CETN2 complex to distorted DNA is enhanced in the presence of the DDB1:DDB2 complex, also known as the UV-DDB complex. The UV-DDB complex preferentially binds UV-generated lesions, such as pyrimidine-pyrimidone photodimers (6-4 PPDs) and cyclobutane pyrimidine dimers (CPDs), but also recognizes DNA with apurinic/apyrimidinic (AP) sites, and 2-3 bp mismatches (Fujiwara et al. 1999, Wittschieben et al. 2005). The DDB2 subunit of the UV-DDB complex is a WD40 repeat beta-propeller protein. The beta-propeller domain of DDB2 binds the damaged DNA strand (Scrima et al. 2008). The UV-DDB complex is part of a larger ubiquitin ligase complex that, besides DDB1 and DDB2, also contains CUL4A or CUL4B and RBX1 (Groisman et al. 2003, Sugasawa et al. 2005). In the case of 6-4 PPDs and CPDs, UV-DDB binding to damaged DNA probably precedes the binding of the XPC:RAD23:CETN2 complex. However, in the case of 6-4 PPDs, the XPC:RAD23:CETN2 complex may also recognize damaged DNA in the absence of the UV-DDB complex (Fitch et al. 2003, Moser et al. 2005, Wang et al. 2004), but the UV-DDB complex may be important for retention of DNA repair proteins at the DNA damage site (Oh et al. 2011).

The INO80 chromatin remodelling complex positively regulates GG-NER. INO80 and ACTR5 (ARP5) subunits of the INO80 complex are enriched at GG-NER sites, probably via interaction with DDB1. Chromatin relaxation by the INO80 complex at DNA damage site may be necessary for XPC recruitment (Jiang et al. 2010). In yeast, the interaction between INO80 and the orthologs of XPC and RAD23 has been reported and it was suggested that this interaction is important for the restoration of chromatin structure after GG-NER completion (Sarkar et al. 2010).

Literature References
PubMed ID Title Journal Year
21388382 Nucleotide excision repair proteins rapidly accumulate but fail to persist in human XP-E (DDB2 mutant) cells

Tamura, D, Emmert, S, Oh, KS, DiGiovanna, JJ, Kraemer, KH, Imoto, K

Photochem. Photobiol. 2011
19609301 Two-stage dynamic DNA quality check by xeroderma pigmentosum group C protein

Clement, FC, Naegeli, H, Ferrando-May, E, Fei, J, Leitenstorfer, A, Träutlein, D, Camenisch, U

EMBO J. 2009
14742321 UV radiation-induced XPC translocation within chromatin is mediated by damaged-DNA binding protein, DDB2

Wang, QE, Zhu, Q, Wani, G, Chen, J, Wani, AA

Carcinogenesis 2004
15882621 UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex

Okuda, Y, Mori, T, Tanaka, K, Saijo, M, Tanaka, K, Iwai, S, Matsuda, N, Sugasawa, K, Hanaoka, F, Nishi, R, Chu, G

Cell 2005
12732143 The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage

Drapkin, R, Kuraoka, I, Polanowska, J, Kisselev, AF, Tanaka, K, Saijo, M, Sawada, J, Groisman, R, Nakatani, Y

Cell 2003
17882165 Recognition of DNA damage by the Rad4 nucleotide excision repair protein

Pavletich, NP, Min, JH

Nature 2007
16223728 DDB1-DDB2 (xeroderma pigmentosum group E) protein complex recognizes a cyclobutane pyrimidine dimer, mismatches, apurinic/apyrimidinic sites, and compound lesions in DNA

Wood, RD, Wittschieben, BØ, Iwai, S

J. Biol. Chem. 2005
10391953 Characterization of DNA recognition by the human UV-damaged DNA-binding protein

Mizukoshi, T, Fujiwara, Y, Iwai, S, Masutani, C, Kondo, J, Hanaoka, F

J. Biol. Chem. 1999
20855601 INO80 chromatin remodeling complex promotes the removal of UV lesions by the nucleotide excision repair pathway

Jiang, Y, Li, L, Guo, R, Wang, X, Johnson, DG, Bao, S, Shen, X

Proc. Natl. Acad. Sci. U.S.A. 2010
15811629 The UV-damaged DNA binding protein mediates efficient targeting of the nucleotide excision repair complex to UV-induced photo lesions

Alekseev, S, Yasui, A, Mullenders, LH, Volker, M, Moser, J, Kool, H, van Zeeland, AA, Vrieling, H

DNA Repair (Amst.) 2005
19109893 Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex

Jeffrey, PD, Czyzewski, BK, Iwai, S, Kawasaki, Y, Thomä, NH, Groisman, R, Pavletich, NP, Konícková, R, Scrima, A, Nakatani, Y

Cell 2008
21135142 The Ino80 chromatin-remodeling complex restores chromatin structure during UV DNA damage repair

McHugh, PJ, Kiely, R, Sarkar, S

J. Cell Biol. 2010
12944386 In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product

Nakajima, S, Ford, JM, Yasui, A, Fitch, ME

J. Biol. Chem. 2003
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