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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.<\/jats:p>","DOI":"10.1083\/jcb.202508059","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T06:21:15Z","timestamp":1773123675000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["HSF2-HSP110 axis supports genome stability via RNA polymerase II transcription and DNA repair"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7835-0065","authenticated-orcid":true,"given":"Xiongjie","family":"Jin","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012mef835","id-type":"ROR","asserted-by":"publisher"}],"name":"Georgia Cancer Center, Augusta University, Medical College of Georgia 1 Department of Radiation Oncology, , Augusta, GA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3668-4852","authenticated-orcid":true,"given":"Caixia","family":"Xi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012mef835","id-type":"ROR","asserted-by":"publisher"}],"name":"Georgia Cancer Center, Augusta University, Medical College of Georgia 1 Department of Radiation Oncology, , Augusta, GA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3043-7608","authenticated-orcid":true,"given":"Bhaumik","family":"Pandya","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012mef835","id-type":"ROR","asserted-by":"publisher"}],"name":"Georgia Cancer Center, Augusta University, Medical College of Georgia 2 , Augusta, GA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6794-2647","authenticated-orcid":true,"given":"Junfeng","family":"Pang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012mef835","id-type":"ROR","asserted-by":"publisher"}],"name":"Georgia Cancer Center, Augusta University 3 , Augusta, GA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5282-7806","authenticated-orcid":true,"given":"Diego","family":"Fernandez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012mef835","id-type":"ROR","asserted-by":"publisher"}],"name":"Georgia Cancer Center, Augusta University 3 , Augusta, GA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4483-8986","authenticated-orcid":true,"given":"Binnur","family":"Eroglu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012mef835","id-type":"ROR","asserted-by":"publisher"}],"name":"Georgia Cancer Center, Augusta University 3 , Augusta, GA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3240-9803","authenticated-orcid":true,"given":"Demetrius","family":"Moskophidis","sequence":"additional","affiliation":[{"name":"4Department of Medicine, Medical College of Georgia, Georgia Cancer Center, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3510-9968","authenticated-orcid":true,"given":"Nahid F.","family":"Mivechi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012mef835","id-type":"ROR","asserted-by":"publisher"}],"name":"Georgia Cancer Center, Augusta University, Medical College of Georgia 1 Department of Radiation Oncology, , Augusta, GA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"2026041709440293600_bib1","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.molcel.2012.04.009","article-title":"R loops: From transcription byproducts to threats to genome stability","volume":"46","author":"Aguilera","year":"2012","journal-title":"Mol. 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