Dual regulation of transcription factor binding by tup11/12-mediated destabilization and DNA loop-mediated stabilization ensures stress-specific gene activation in fission yeast.

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.