HSF2-HSP110 axis supports genome stability via RNA polymerase II transcription and DNA repair

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.