Deformations of Promoter DNA Bound to Carcinogens Help Interpret Effects on
TATA-element Structure and Activity
The TATA-Box Binding Protein (TBP) is required by eukaryotic RNA polymerases for correct
transcription initiation. TBP binds to the the minor groove of an 8-basepair (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-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 adducts 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 twelve 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 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 phenylalanines 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 great difficulty
(due to interference with TATA/TBP interactions). The unraveled 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.
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