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 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 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 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.
Department of Chemistry and Courant Institute of Mathematical Sciences, New York University and the Howard Hughes Medical Institute, 251 Mercer Street, New York, NY 10012, USA.
Qing
Q
Zhang
Suse
S
Broyde
Tamar
T
Schlick
D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000737:chemistry*; D001665:Binding Sites; D002273:Carcinogens / Q000737:chemistry*; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000648:ultrastructure; D004249:DNA Damage; D004548:Elasticity; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009038:Motion; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D011401:Promoter Regions, Genetic; D013314:Stress, Mechanical; D013329:Structure-Activity Relationship; D016385:TATA Box; D035181:TATA-Box Binding Protein / Q000737:chemistry*; D019415:Torque
D002273:Carcinogens; D035181:TATA-Box Binding Protein; D001564:Benzo(a)pyrene; D004247:DNA