Base pair conformation-dependent excision of benzo[a]pyrene diol epoxide-guanine adducts by human nucleotide excision repair enzymes

Martin T. Hess, Daniela Gunz, Natalia Luneva, Nicholas Geacintov, Hanspeter Naegeli

Research output: Contribution to journalArticle

Abstract

Human nucleotide excision repair processes carcinogen-DNA adducts at highly variable rates, even at adjacent sites along individual genes. Here, we identify, conformational determinants of fast or slow repair by testing excision of N2-guanine adducts formed by benzo[a]pyrene diol epoxide (BPDE), a potent and ubiquitous mutagen that induces mainly G- C→T · A transversions and frameshift deletions. We found that human nucleotide excision repair processes the predominant (+)-trans-BPDE-N2-dG adduct 15 times less efficiently than a standard acetylaminofluorene-C8-dG lesion in the same sequence. No difference was observed between (+)-trans- and (-)- trans-BPDE-N2-dG, but excision was enhanced about 10-fold by changing the adduct configurations to either (+)-cis- or (-)-cis-BPDE-N2-dG. Conversely, excision of (+)-cis- and (-)-cis-but not (+)-trans-BPDE-N2-dG was reduced about 10-fold when the complementary cytosine was replaced by adenine, and excision of these BPDE lesions was essentially abolished when the complementary deoxyribonucleotide was missing. Thus, a set of chemically identical BPDE adducts yielded a greater-than-100-fold range of repair rates, demonstrating that nucleotide excision repair activity is entirely dictated by local DNA conformation. In particular, this unique comparison between structurally highly defined substrates shows that fast excision of BPDE-N2- dG lesions is correlated with displacement of both the modified guanine and its partner base in the complementary strand from their normal intrahelical positions. The very slow excision of carcinogen-DNA adducts located opposite deletion sites reveals a cellular strategy that minimizes the fixation of frameshifts after mutagenic translesion synthesis.

Original languageEnglish (US)
Pages (from-to)7069-7076
Number of pages8
JournalMolecular and Cellular Biology
Volume17
Issue number12
StatePublished - Dec 1997

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Benzo(a)pyrene
Epoxy Compounds
Guanine
Base Pairing
DNA Repair
Enzymes
DNA Adducts
Carcinogens
Deoxyribonucleotides
Nucleic Acid Conformation
Cytosine
Mutagens
Adenine
Genes

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Base pair conformation-dependent excision of benzo[a]pyrene diol epoxide-guanine adducts by human nucleotide excision repair enzymes. / Hess, Martin T.; Gunz, Daniela; Luneva, Natalia; Geacintov, Nicholas; Naegeli, Hanspeter.

In: Molecular and Cellular Biology, Vol. 17, No. 12, 12.1997, p. 7069-7076.

Research output: Contribution to journalArticle

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