Covalent polycyclic aromatic hydrocarbon-DNA adducts: Carcinogenicity, structure, and function

Suse Broyde, Lihua Wang, Yuqin Cai, Lei Jia, Robert Shapiro, Dinshaw J. Patel, Nicholas E. Geacintov

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are environmental carcinogens whose metabolites can react with DNA to form bulky DNA adducts. We focus on the well-studied planar bay-region PAH benzo[a]pyrene (B[a]P) and on the twisted, fjord-region PAHs dibenzo[a,l]pyrene (DB[a,l]P), benzo[g]chrysene (B[g]C), and benzo[c]phenanthrene (B[c]Ph). The unusually potent tumorigenicity of the fjord-region carcinogens, particularly DB[a,l]P, is noted. DNA adducts derived from the selected prototypes are then described. Mutagenic properties of these lesions are briefly considered as anchors for their connection to cancer initiation. We next describe structural characteristics of the bulky adducts as determined in solution by NMR methods and computational treatments. Structure-function relationships are subsequently discussed. We connect solution structures to observed relative susceptibilities to nucleotide excision repair (NER) with human HeLa cell extracts, as NER is the fundamental defense against bulky adducts in humans. Processing of the bulky lesions by DNA polymerases in connection with lesion mutagenicity is also considered. Finally, we offer perspectives concerning adduct structures in relation to cancer prevention and treatment, and the need for deeper understanding of the processing of structurally different lesions on cellular and systems biology levels.

Original languageEnglish (US)
Title of host publicationChemical Carcinogenesis
EditorsTrevor Penning
Pages181-207
Number of pages27
DOIs
StatePublished - 2011

Publication series

NameCurrent Cancer Research
Volume6
ISSN (Print)0940-0745

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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