Dual Regulation of Transcription Factor Binding by Tup11/12-Mediated Destabilisation and DNA Loop-Mediated Stabilisation 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 elucidate 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 occurred, which required the TFs Atf1 and Rst2-both essential for fbp1 induction. Moreover, this aberrant fbp1 activation was diminished by the loss of Php5, a factor indispensable for DNA-loop formation between the binding sites of Atf1 and Rst2. The defective nonspecific transcription in the tup11-delta/tup12-delta/php5-delta mutant was restored when Atf- and Rst2-binding sites were artificially positioned in proximity, indicating that reciprocal stabilisation 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 destabilisation and DNA loop-mediated stabilisation. The synergistic reduction observed in stress tolerance in the tup11-delta/tup12-delta/php5-delta mutant further suggests that this dual regulatory mechanism is crucial for cellular adaptation to environmental stresses.