The structure of Rad4/Rad23, the yeast homolog of the human nucleotide excision repair (NER) lesion recognition factor XPC (Min and Pavletich, (2007) Nature 449:570-575) reveals that the lesion's partner base is flipped into the enzyme as one component of the recognition process.  This suggests the hypothesis that lesion-partner base-flipping free energy profiles reflect a thermodynamic property sensed by the recognition protein.  We present complete profiles for two lesions derived from the procarcinogenic polycyclic aromatic hydrocarbons, dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P), namely, R-DB[a,l]P-N6-dA and R-B[a]P-N6-dA, and the unmodified duplex; we integrate these results with our prior profiles for R-DB[a,l]P-dG (Zheng et al, (2010) Chem. Res. Toxicol. 23:1868-1870).  All adopt conformational themes involving intercalation of the aromatic ring system into the DNA duplex but differ in details. Our results show that relative NER susceptibilities follow the trend of relative flipping free energy barriers, and lesion modeling into Rad4/Rad23 has provided further insights into the recognition process. (Supported by NIH Grants CA-28038 to S.B., and  CA-099194 to N.E.G.)

Free energy profiles of base-flipping in intercalative PAH-damaged duplexes: Energetic and structural relationships to  NER susceptibility

246th National Meeting (2013)

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