Dual regulation of transcription factor binding by tup11/12-mediated destabilization and DNA loop-mediated...

An appropriate transcriptional response to external stresses is crucial for all organisms. Gene expression is regulated by transcription factors (TFs) binding to specific DNA cis-elements. However, how individual TFs achieve stress-specific binding remains elusive. Here we examine the molecular basis of the stress-specific transcriptional response of the Schizosaccharomyces pombe fbp1 gene. The fbp1 gene is activated upon glucose starvation, with transcriptional co-repressors Tup11 and Tup12 playing pivotal roles in maintaining stress-specificity. In the absence of Tup11 and Tup12, nonspecific activation of fbp1 transcription occurs, which requires the TFs Atf1 and Rst2-both essential for fbp1 induction. Moreover, this aberrant fbp1 activation is diminished by the loss of Php5, a factor indispensable for DNA-loop formation between Atf1- and Rst2-binding sites. The defective nonspecific transcription in the tup11∆/tup12∆/php5∆ mutant is restored when Atf1- and Rst2-binding sites are artificially positioned in proximity to each other, indicating that reciprocal stabilization between these TFs facilitates their binding. These findings demonstrate that fbp1 achieves stress-specific transcriptional activation through the counteractive regulation of TF-binding: Tup11/12-mediated destabilization and DNA loop-mediated stabilization. The synergistic reduction in stress tolerance observed in the tup11∆/tup12∆/php5∆ mutant further suggests that this dual regulatory mechanism is crucial for cellular adaptation to environmental stresses.