Dataset Information

Stereochemistry and position-dependent effects of carcinogens on TATA/TBP binding.

ABSTRACT: The TATA-box binding protein (TBP) is required by eukaryotic RNA polymerases to bind to the TATA box, an eight-basepair DNA promoter element, to initiate transcription. Carcinogen adducts that bind to the TATA box can hamper this important process. Benzo[a]pyrene (BP) is a representative chemical carcinogen that can be metabolically converted to highly reactive benzo[a]pyrene diol epoxides (BPDE), which in turn can form chemically stereoisomeric BP-DNA adducts. Depending on the TATA-bound adduct's location and stereochemistry, TATA/TBP binding can be decreased or increased. Our previous study interpreted the location-dependent effect in terms of conformational freedom and major-groove space available to BP. Here we further explore specific structural changes of the TATA/TBP complex to help interpret the stereochemical effect in terms of the flexibility of the TATA bases that frame the intercalated adduct. Thermodynamic analyses using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) yield large standard deviations, which make the computed binding free energies the same within the error bars and point to current limitations of free energy calculations of large and highly charged systems like DNA/protein complexes.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC1386768 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Stereochemistry and position-dependent effects of carcinogens on TATA/TBP binding.

Zhang Qing Q Schlick Tamar T

Biophysical journal 20051230 6

The TATA-box binding protein (TBP) is required by eukaryotic RNA polymerases to bind to the TATA box, an eight-basepair DNA promoter element, to initiate transcription. Carcinogen adducts that bind to the TATA box can hamper this important process. Benzo[a]pyrene (BP) is a representative chemical carcinogen that can be metabolically converted to highly reactive benzo[a]pyrene diol epoxides (BPDE), which in turn can form chemically stereoisomeric BP-DNA adducts. Depending on the TATA-bound adduct ...[more]

PMID: 16387764

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Project description:The formation of sequence-specific complexes of TATA binding protein (TBP) with the minor groove of DNA results in the burial of large nonpolar surfaces and the exclusion of water from these interfaces. The release of water is thus expected to provide a significant entropic driving force for formation of the transcription-preinitiated complexes mediated by the binding of TBP to specific sequences. In this article are described equilibrium-binding studies of Saccharomyces cerevisiae TBP to 14 bp oligonucleotides bearing either the tightly bound and efficiently transcribed adenovirus major late promoter (TATAAAAG) or its inosine-substituted derivative (TITIIIIG) as a function of neutral osmolyte concentration. These two DNA sequences present the same pattern of minor groove hydrogen-bond donors and acceptors to the protein. TBP-DNA complex formation was monitored by steady-state fluorescence resonance energy transfer measurements of the oligonucleotides end-labeled with fluorescein (donor) and TAMRA (acceptor). Correct interpretation of the results obtained with the inosine-substituted sequence required careful consideration of the optical properties of the dyes as a function of osmolyte concentration to demonstrate that the relative change in the end-to-end distances for TATAAAAG- and TITIIIIG-bearing oligonucleotides is the same upon TBP binding. Although the affinity of TBP is slightly greater for the adenosine compared with the inosine-substituted TATA sequence in the absence of osmolyte, the end-to-end distances of the bound DNA in complex with TBP, the enthalpic and electrostatic components of binding, are identical within experimental precision. However, approximately 18 additional molecules of water are released upon TBP binding the TATAAAAG as compared with the TITIIIIG sequence resulting in an entropic advantage to the binding of the natural promoter sequence. These results are considered with regard to differences in the flexibility and hydration of the two DNA sequences.

Dataset Information

Stereochemistry and position-dependent effects of carcinogens on TATA/TBP binding.

Publications

Stereochemistry and position-dependent effects of carcinogens on TATA/TBP binding.

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