The relationships between XPC binding to conformationally diverse DNA adducts and their excision by the human NER system: Is there a correlation?

Yuan Cho Lee, Yuqin Cai, Hong Mu, Suse Broyde, Shantu Amin, Xuejing Chen, Jung Hyun Min, Nicholas E. Geacintov

Research output: Contribution to journalArticle

Abstract

The first eukaryotic NER factor that recognizes NER substrates is the heterodimeric XPC-RAD23B protein. The currently accepted hypothesis is that this protein recognizes the distortions/destabilization caused by DNA lesions rather than the lesions themselves. The resulting XPC-RAD23B-DNA complexes serve as scaffolds for the recruitment of subsequent NER factors that lead to the excision of the oligonucleotide sequences containing the lesions. Based on several well-known examples of DNA lesions like the UV radiation-induced CPD and 6-4 photodimers, as well as cisplatin-derived intrastrand cross-linked lesions, it is generally believed that the differences in excision activities in human cell extracts is correlated with the binding affinities of XPC-RAD23B to these DNA lesions. However, using electrophoretic mobility shift assays, we have found that XPC-RAD23B binding affinities of certain bulky lesions derived from metabolically activated polycyclic aromatic hydrocarbon compounds such as benzo[. a]pyrene and dibenzo[. a,. l]pyrene, are not directly, or necessarily correlated with NER excision activities observed in cell-free extracts. These findings point to features of XPC-RAD23B-bulky DNA adduct complexes that may involve the formation of NER-productive or unproductive forms of binding that depend on the structural and stereochemical properties of the DNA adducts studied. The pronounced differences in NER cleavage efficiencies observed in cell-free extracts may be due to differences in the successful recruitment of subsequent NER factors by the XPC-RAD23B-DNA adduct complexes, and/or in the verification step. These phenomena appear to depend on the structural and conformational properties of the class of bulky DNA adducts studied.

Original languageEnglish (US)
Pages (from-to)55-63
Number of pages9
JournalDNA Repair
Volume19
DOIs
StatePublished - Jul 2014

Keywords

  • Benzo[a]pyrene
  • DNA adduct
  • Dibenzo[a,l]pyrene
  • Electrophoretic mobility shift assay
  • Nucleotide excision repair (NER)
  • XPC-RAD23B binding

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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