Published online 30 April 2004
Nucleic Acids Research, 2004, Vol. 32, No. 8 2474-2481
© 2004 Oxford University Press
NMR structure of the DNA decamer duplex containing double T·G mismatches of cis–syn cyclobutane pyrimidine dimer: implications for DNA damage recognition by the XPC–hHR23B complex
Department of Chemistry and National Creative Research Initiative Center, Korea Advanced Institute of Science and Technology, 373–1, Guseong-dong, Yuseong-gu, Daejon 305–701, Korea and 1 Institute for Protein Research, Osaka University, 3–2 Yamadaoka, Suita, 565–0871 Japan
*To whom correspondence should be addressed. Tel: +82 42 869 2828; Fax: +82 42 869 2810; Email: byongseok.choi{at}kaist.ac.kr
Present address:
Joon-Hwa Lee, Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309, USA
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
Received March 17, 2004; Accepted April 6, 2004
The cis–syn cyclobutane pyrimidine dimer (CPD) is a cytotoxic, mutagenic and carcinogenic DNA photoproduct and is repaired by the nucleotide excision repair (NER) pathway in mammalian cells. The XPC–hHR23B complex as the initiator of global genomic NER binds to sites of certain kinds of DNA damage. Although CPDs are rarely recognized by the XPC–hHR23B complex, the presence of mismatched bases opposite a CPD significantly increased the binding affinity of the XPC–hHR23B complex to the CPD. In order to decipher the properties of the DNA structures that determine the binding affinity for XPC–hHR23B to DNA, we carried out structural analyses of the various types of CPDs by NMR spectroscopy. The DNA duplex which contains a single 3' T·G wobble pair in a CPD (CPD/GA duplex) induces little conformational distortion. However, severe distortion of the helical conformation occurs when a CPD contains double T·G wobble pairs (CPD/GG duplex) even though the T residues of the CPD form stable hydrogen bonds with the opposite G residues. The helical bending angle of the CPD/GG duplex was larger than those of the CPD/GA duplex and properly matched CPD/AA duplex. The fluctuation of the backbone conformation and significant changes in the widths of the major and minor grooves at the double T·G wobble paired site were also observed in the CPD/GG duplex. These structural features were also found in a duplex that contains the (6–4) adduct, which is efficiently recognized by the XPC–hHR23B complex. Thus, we suggest that the unique structural features of the DNA double helix (that is, helical bending, flexible backbone conformation, and significant changes of the major and/or minor grooves) might be important factors in determining the binding affinity of the XPC–hHR23B complex to DNA.
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