The HSF2-HSP110 Axis Promotes Genome Stability by Supporting RNA Polymerase II Dependent Transcription and DNA Repair Gene Expression [PRO-Seq]

Here, we identify a previously unrecognized genotoxic stressresponsive transcriptional axis composed of Heat Shock Factor 2 (HSF2) and its client chaperone HSP110, which is activated by ionizing radiation (IR). Loss of HSF2 or HSP110 leads to increased DNA damage and heightened IR sensitivity.

Mechanistically, the HSF2-HSP110 axis safeguards genome stability by sustaining RNAPII processivity and its C-terminal domain (CTD) phosphorylation, particularly at serine 7 (S7). Disruption of this axis leads to transcriptional dysregulation, altered pre-mRNA splicing, increased transcription-replication conflict, and downregulation of DNA damage response genes, resulting in DNA damage. In vivo, loss of HSF2 accelerates IR-induced lymphomagenesis by impairing transcriptional regulation, specifically inhibiting DNA repair gene expression.