The precise regulation of RNA polymerase II (RNAPII) is essential for transcriptional fidelity and genome stability. Here, we identify a previously unrecognized genotoxic stress-responsive transcriptional axis composed of heat shock factor 2 (HSF2) and its client chaperone HSP110, which is activated by x-irradiation (ionizing irradiation IR). Loss of HSF2 or HSP110 increases DNA damage and heightens IR sensitivity. Mechanistically, the HSF2-HSP110 axis safeguards genome stability by sustaining RNAPII function, specifically its processivity and C-terminal domain (CTD) phosphorylation at serine 7, which are critical for efficient transcription. Consequently, disruption of this axis causes transcriptional dysregulation, conflicts during DNA replication, altered pre-mRNA splicing, and reduced levels of DNA repair genes, resulting in sustained DNA damage. In vivo, loss of HSF2 accelerates development of IR-induced T cell lymphoma by impairing transcriptional regulation, leading to inhibition of DNA repair gene expression. These findings define the HSF2-HSP110 axis as a critical transcriptional mechanism in the genotoxic stress response and suggest a therapeutic vulnerability for sensitizing tumors to genotoxic therapies.
Jin et al. (Tue,) studied this question.