Genome-wide binding preferences of the key components of eukaryotic preinitiation complex (PIC) have been recently measured at high resolution in Saccharomyces cerevisiae by Rhee and Pugh. However, the rules determining the PIC binding specificity remain poorly understood. In this study, we show that nonconsensus protein-DNA binding significantly influences PIC binding preferences. We estimate that such nonconsensus binding contributes statistically at least 2-3 kcal/mol (on average) of additional attractive free energy per protein per core-promoter region. The predicted attractive effect is particularly strong at repeated poly(dA:dT) and poly(dC:dG) tracts. Overall, the computed free-energy landscape of nonconsensus protein-DNA binding shows strong correlation with the measured genome-wide PIC occupancy. Remarkably, statistical PIC preferences of binding to both TFIID-dominated and SAGA-dominated genes correlate with the nonconsensus free-energy landscape, yet these two groups of genes are distinguishable based on the average free-energy profiles. We suggest that the predicted nonconsensus binding mechanism provides a genome-wide background for specific promoter elements, such as transcription-factor binding sites, TATA-like elements, and specific binding of the PIC components to nucleosomes. We also show that nonconsensus binding has genome-wide influence on transcriptional frequency.
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