GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE326nnn/GSE326884/primaryOK200OtherHomo sapiensOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE326884GEOGSEfalseThe HSF2-HSP110 Axis Promotes Genome Stability by Supporting RNA Polymerase II Dependent Transcription and DNA Repair Gene Expression [PRO-Seq]The precise regulation of RNA polymerase II (RNAPII) is essential for transcriptional fidelity and genome stability. 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. These findings define the HSF2-HSP110 axis as an essential transcriptional mechanism in the genotoxic stress response and reveal a therapeutic vulnerability that could be exploited to sensitize tumors to genotoxic therapies.2026/05/01GSE326884GSM9642058GSM9642061GSM9642060GSM964205920301326884Homo sapiens