Deformations of promoter DNA bound to carcinogens help interpret effects on TATA-element structure and activity

Research output: Contribution to journalArticle

Abstract

The TATA-box binding protein (TBP) is required by eukaryotic RNA polymerases for correct transcription initiation. TBP binds to the minor groove of an 8 base pair (bp) DNA-promoter element known as the TATA box and severely bends the TATA box. The promoter-DNA substrate can be damaged by components present in the cell or the environment to produce covalent carcinogen-DNA adducts. These may lead to transcription blockage or unfaithful transcription. Benzo[a]pyrene (BP) is a widespread environmental chemical carcinogen which can be metabolically converted to DNA-reactive enantiomeric (+) and (-)-anti-benzo[a]pyrene diol epoxides (BPDEs). Recent experimental studies of a pair of stereoisomeric adenine adducts, derived from (+) and (-)-anti-BPDEs, have revealed how these lesions influence the complexation of TBP with the TATA box. Depending on the adduct's location in the TATA box and its stereochemistry, the stability of monomeric TATA-TBP complexes was found to increase or decrease relative to the unmodified DNA. We report here analyses of molecular-dynamics simulations to interpret these findings. Structural analyses of 12 DNA-protein systems representing different combinations of adduct stereoisomer type and placement within the promoter reveal that the location of the adduct within the TATA octamer determines whether the stability of TATA-TBP complexes is increased or decreased. The effect on binding stability can be interpreted in terms of conformational freedom and major-groove space available to BP due to the hydrogen bonds and inserted phenylalanin.es of the TATA-TBP complex; that is, depending on the position of the adenine to which BP is covalently bound, BP can be accommodated in an intercalated or major-groove orientation with ease or with difficulty (due to interference with TATA-TBP interactions). The unravelled structures and interactions thus reveal the effect of different adduct locations on TATA-TBP complex formation and suggest how transcription initiation may be affected by the presence of a bulky BP.

Original languageEnglish (US)
Pages (from-to)1479-1496
Number of pages18
JournalPhilosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences
Volume362
Issue number1820
DOIs
StatePublished - Jul 15 2004

Keywords

  • Benzo[a]pyrene diol epoxide
  • Molecular-dynamics simulation
  • Stereochemistry
  • TATA box
  • TBP
  • Transcription initiation

ASJC Scopus subject areas

  • Mathematics(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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