2lzk Citations

Nuclear Magnetic Resonance Solution Structure of an N(2)-Guanine DNA Adduct Derived from the Potent Tumorigen Dibenzo[a,l]pyrene: Intercalation from the Minor Groove with Ruptured Watson-Crick Base Pairing.


The most potent tumorigen identified among the polycyclic aromatic hydrocarbons (PAH) is the nonplanar fjord region dibenzo[a,l]pyrene (DB[a,l]P). It is metabolically activated in vivo through the widely studied diol epoxide (DE) pathway to form covalent adducts with DNA bases, predominantly guanine and adenine. The (+)-11S,12R,13R,14S DE enantiomer forms adducts via its C14 position with the exocyclic amino group of guanine. Here, we present the first nuclear magnetic resonance solution structure of a DB[a,l]P-derived adduct, the 14R-(+)-trans-anti-DB[a,l]P-N(2)-dG (DB[a,l]P-dG) lesion in double-stranded DNA. In contrast to the stereochemically identical benzo[a]pyrene-derived N(2)-dG adduct (B[a]P-dG) in which the B[a]P rings reside in the B-DNA minor groove on the 3'-side of the modifed deoxyguanosine, in the DB[a,l]P-derived adduct the DB[a,l]P rings intercalate into the duplex on the 3'-side of the modified base from the sterically crowded minor groove. Watson-Crick base pairing of the modified guanine with the partner cytosine is broken, but these bases retain some stacking with the bulky DB[a,l]P ring system. This new theme in PAH DE-DNA adduct conformation differs from (1) the classical intercalation motif in which Watson-Crick base pairing is intact at the lesion site and (2) the base-displaced intercalation motif in which the damaged base and its partner are extruded from the helix. The structural considerations that lead to the intercalated conformation of the DB[a,l]P-dG lesion in contrast to the minor groove alignment of the B[a]P-dG adduct, and the implications of the DB[a,l]P-dG conformational motif for the recognition of such DNA lesions by the human nucleotide excision repair apparatus, are discussed.

Reviews citing this publication (1)

  1. Repair-Resistant DNA Lesions. Geacintov NE, Broyde S. Chem. Res. Toxicol. 30 1517-1548 (2017)

Articles citing this publication (8)

  1. Adenine-DNA adducts derived from the highly tumorigenic Dibenzo[a,l]pyrene are resistant to nucleotide excision repair while guanine adducts are not. Kropachev K, Kolbanovskiy M, Liu Z, Cai Y, Zhang L, Schwaid AG, Kolbanovskiy A, Ding S, Amin S, Broyde S, Geacintov NE. Chem. Res. Toxicol. 26 783-793 (2013)
  2. The relationships between XPC binding to conformationally diverse DNA adducts and their excision by the human NER system: is there a correlation? Lee YC, Cai Y, Mu H, Broyde S, Amin S, Chen X, Min JH, Geacintov NE. DNA Repair (Amst.) 19 55-63 (2014)
  3. Free energy profiles of base flipping in intercalative polycyclic aromatic hydrocarbon-damaged DNA duplexes: energetic and structural relationships to nucleotide excision repair susceptibility. Cai Y, Zheng H, Ding S, Kropachev K, Schwaid AG, Tang Y, Mu H, Wang S, Geacintov NE, Zhang Y, Broyde S. Chem. Res. Toxicol. 26 1115-1125 (2013)
  4. Transition state in DNA polymerase β catalysis: rate-limiting chemistry altered by base-pair configuration. Oertell K, Chamberlain BT, Wu Y, Ferri E, Kashemirov BA, Beard WA, Wilson SH, McKenna CE, Goodman MF. Biochemistry 53 1842-1848 (2014)
  5. Nuclear magnetic resonance studies of an N2-guanine adduct derived from the tumorigen dibenzo[a,l]pyrene in DNA: impact of adduct stereochemistry, size, and local DNA sequence on solution conformations. Rodríguez FA, Liu Z, Lin CH, Ding S, Cai Y, Kolbanovskiy A, Kolbanovskiy M, Amin S, Broyde S, Geacintov NE. Biochemistry 53 1827-1841 (2014)
  6. Real-time surface plasmon resonance study of biomolecular interactions between polymerase and bulky mutagenic DNA lesions. Xu L, Vaidyanathan VG, Cho BP. Chem. Res. Toxicol. 27 1796-1807 (2014)
  7. Adenine versus guanine DNA adducts of aristolochic acids: role of the carcinogen-purine linkage in the differential global genomic repair propensity. Kathuria P, Sharma P, Wetmore SD. Nucleic Acids Res. 43 7388-7397 (2015)
  8. Cyclodextrin-promoted Diels Alder reactions of a polycyclic aromatic hydrocarbon under mild reaction conditions. Chaudhuri S, Phelan T, Levine M. Tetrahedron Lett. 56 1619-1623 (2015)