TY - JOUR
T1 - Relating repair susceptibility of carcinogen-damaged DNA with structural distortion and thermodynamic stability
AU - Wu, Min
AU - Yan, Shixiang
AU - Patel, Dinshaw J.
AU - Geacintov, Nicholas E.
AU - Broyde, Suse
N1 - Funding Information:
This research is supported by NIH Grant CA-28038 to S.B., NIH Grants CA-76660 and CA-20851 to N.E.G. and NIH Grant CA-46533 to D.J.P. Computations were carried out at the National Science Foundation (NSF) San Diego Supercomputer Center, the NSF Advanced Computing Center for Engineering and Science at the University of Texas at Austin, the Department of Energy (DOE) National Energy Research Super Computing Center and on our own SGI workstations.
PY - 2002/8/1
Y1 - 2002/8/1
N2 - A key issue in the nucleotide excision repair (NER) of bulky carcinogen-DNA adducts is the ability of the NER machinery to recognize and repair certain adducts while failing to repair others. Unrepaired adducts can survive to cause mutations that initiate the carcinogenic process. Benzo[c]phenanthrene (B[c]Ph), a representative fjord region polycyclic aromatic hydrocarbon, can be metabolically activated to the enantiomeric benzo[c]phenanthrene diol epoxides (B[c]PhDEs), (+)-(1S,2R,3R,4S)-3,4-dihydroxy-1, 2-epoxy-1,2,3,4- tetrahydrobenzo[c]phenanthrene and the corresponding (-)-(1R,2S,3S,4R) isomer. These react predominantly with adenine residues in DNA to produce the stereoisomeric 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts. Duplexes containing the 1R (+) or 1S (-) B[c]Ph-dA adduct in codon 61 of the human N-ras mutational hotspot sequence CA*A, with B[c]Ph modification at A* are not repaired by the human NER system. However, the analogous stereoisomeric DNA adducts of the bay region benzo[a]pyrene diol epoxide (B[a]PDE), 10S (+)- and 10R (-)-trans-anti-B[a]P-N6-dA, are repaired in the same base sequence. In order to elucidate structural and thermodynamic origins of this phenomenon, we have carried out a 2 ns molecular dynamics simulation for the 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts in an 11mer duplex containing the human N-ras codon 61 sequence, and compared these results with our previous study of the B[a]P-dA adducts in the same sequence. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method was applied to calculate the free energies of the pair of stereoisomeric B[c]Ph-dA adducts, and a detailed structural analysis was carried out. The different repair susceptibilities of the B[a]P-dA adducts and the B[c]Ph-dA adducts can be attributed to different degrees of distortion, stemming from combined effects of differences in the quality of Watson-Crick hydrogen bonding, unwinding, stretching and helix backbone perturbations. These differences are due to the different intrinsic topologies of the rigid, planar bay region adducts versus the twisted, sterically hindered fjord region adducts.
AB - A key issue in the nucleotide excision repair (NER) of bulky carcinogen-DNA adducts is the ability of the NER machinery to recognize and repair certain adducts while failing to repair others. Unrepaired adducts can survive to cause mutations that initiate the carcinogenic process. Benzo[c]phenanthrene (B[c]Ph), a representative fjord region polycyclic aromatic hydrocarbon, can be metabolically activated to the enantiomeric benzo[c]phenanthrene diol epoxides (B[c]PhDEs), (+)-(1S,2R,3R,4S)-3,4-dihydroxy-1, 2-epoxy-1,2,3,4- tetrahydrobenzo[c]phenanthrene and the corresponding (-)-(1R,2S,3S,4R) isomer. These react predominantly with adenine residues in DNA to produce the stereoisomeric 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts. Duplexes containing the 1R (+) or 1S (-) B[c]Ph-dA adduct in codon 61 of the human N-ras mutational hotspot sequence CA*A, with B[c]Ph modification at A* are not repaired by the human NER system. However, the analogous stereoisomeric DNA adducts of the bay region benzo[a]pyrene diol epoxide (B[a]PDE), 10S (+)- and 10R (-)-trans-anti-B[a]P-N6-dA, are repaired in the same base sequence. In order to elucidate structural and thermodynamic origins of this phenomenon, we have carried out a 2 ns molecular dynamics simulation for the 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts in an 11mer duplex containing the human N-ras codon 61 sequence, and compared these results with our previous study of the B[a]P-dA adducts in the same sequence. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method was applied to calculate the free energies of the pair of stereoisomeric B[c]Ph-dA adducts, and a detailed structural analysis was carried out. The different repair susceptibilities of the B[a]P-dA adducts and the B[c]Ph-dA adducts can be attributed to different degrees of distortion, stemming from combined effects of differences in the quality of Watson-Crick hydrogen bonding, unwinding, stretching and helix backbone perturbations. These differences are due to the different intrinsic topologies of the rigid, planar bay region adducts versus the twisted, sterically hindered fjord region adducts.
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U2 - 10.1093/nar/gkf427
DO - 10.1093/nar/gkf427
M3 - Article
C2 - 12140327
AN - SCOPUS:0036682090
SN - 0305-1048
VL - 30
SP - 3422
EP - 3432
JO - Nucleic acids research
JF - Nucleic acids research
IS - 15
ER -