Conformational and Thermodynamic Properties Modulate the Nucleotide Excision Repair of 2-aminofluorene and 2-acetylaminofluorene dG adducts in the NarI Sequence

Authors

Vipin Jain, University of Rhode Island
Benjamin Hilton, University of Rhode Island
Satyakam Patnaik, University of Rhode Island
Yue Zou, University of Rhode Island
M. Paul Chiarelli, University of Rhode Island
Bongsup P. Cho, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

5-1-2012

Department

Biomedical and Pharmaceutical Sciences

Abstract

Nucleotide excision repair (NER) is a major repair pathway that recognizes and corrects various lesions in cellular DNA. We hypothesize that damage recognition is an initial step in NER that senses conformational anomalies in the DNA caused by lesions. We prepared three DNA duplexes containing the carcinogen adduct N-(2'-deoxyguanosin-8-yl)-7-fluoro-2-acetylaminofluorene (FAAF) at G₁, G₂ or G₃ of NarI sequence (5'^_-CCG₁G₂ CG₃CC-3'). Our ¹⁹F-NMR/ICD results showed that FAAF at G₁ and G₃ prefer syn S- and W-conformers, whereas anti B-conformer was predominant for G₂. We found that the repair of FAAF occurs in a conformation-specific manner, i.e. the highly S/W-conformeric G₃ and -G₁ duplexes incised more efficiently than the B-type G₂ duplex (G_{3 ~}G₁>G₂). The melting and thermodynamic data indicate that the S- and W-conformers produce greater DNA distortion and thermodynamic destabilization. The Ndeacetylated N-(2'-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene (FAF) adducts in the same NarI sequence are repaired 2- to 3-fold less than FAAF: however, the incision efficiency was in order of G2~G1>G3, a reverse trend of the FAAF case. We have envisioned the so-called N-acetyl factor as it could raise conformational barriers of FAAF versus FAF. The present results provide valuable conformational insight into the sequence-dependent UvrABC incisions of the bulky aminofluorene DNA adducts.

Citation/Publisher Attribution

Jain, Vilpin, Benjamin Hilton, Satyakam Patnaik, Yue Zhou, M. Paul Chiarelli and Bongsup P. Cho. ʺConformational and Thermodynamic Properties Modulate the Nucleotide Excision Repair of 2-Aninofluorene and 2-Acetylamenofluorene dG Adducts in the Narl Sequences.ʺ Nucleic Acids Research. 40(9):3939-3951. May 1, 2012.

Available at: http://dx.doi.org/10.1093/nar/gkr1307

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