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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE326884 | GEO | 2026/05/01

REPOSITORIES: GEO

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

Project description: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.

2026-05-01 | GSE326894 | GEO

HSF2 Safeguards Against Genomic Instability and Radiation-Induced T-ALL Via Regulation of Pre-mRNA Splicing

Project description:Prompt and accurate responses to DNA damage are crucial for maintaining normal cellular homeostasis and avoiding cell death. These responses involve the activation of DNA repair pathways and changes in gene expression. RNA polymerase II (RNAPII) is responsible for transcribing protein-coding genes and small nuclear RNAs (snRNAs). Concurrent with transcription, pre-mRNA undergoes splicing by the spliceosome, a complex consisting of five ribonucleoproteins (snRNPs), snRNAs, and additional factors, which ensures proper pre-mRNA splicing and generation of mature mRNA, thereby promoting proteome diversity. In this study, we provide new insights into the role of HSF2 in pre-mRNA splicing and maintenance of genomic stability. We observed a significant reduction in RNAPIICTD pS7 following loss of HSF2 and this is accompanied by the inhibition of RNAPII recruitment to snRNA gene promoters and a significant reduction in snRNA transcription. Moreover, the observed reduction in snRNAs expression in cells lacking HSF2 is associated with impaired pre-mRNA splicing and several other consequences. These include a spontaneous increase in DNA damage, enhanced formation of R-loops, and elevated cellular sensitivity to ionizing radiation (IR). These findings suggest that loss of HSF2 leads to multiple disruptions in cellular processes, ultimately resulting in compromised genome stability and increased susceptibility to DNA damage. Furthermore, HSF2-deficient mice exhibit an accelerated IR-induced T cell acute lymphoblastic leukemia (T-ALL), as evidenced by the reduced snRNA levels and expression of IR-induced DNA repair genes. Our findings reveal a previously unrecognized role for HSF2 in the process of snRNA transcription and its loss highlights its pathological consequences. These features are also mirrored by the loss of the HSF2 target gene, HSP110, suggesting that HSP110 contributes, at least in part, to the phenotypes observed following HSF2 loss.

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Project description:Genotoxic damage is known to disrupt cellular functions and is lethal if not repaired properly. We compare the transcriptional programs activated in response to genotoxic DNA damage induced by ionizing radiation (IR) in pre-B cells from mice deficient in various DNA damage response (DDR) genes. We used microarrays to detail the global gene expression of mutated cells compared to WT cells, with and without exposure to the DNA damaging agent ionizing radiation (IR), and identified differentially-regulated genes and associated pathways responding to the damage.

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

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

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

Project description:The HSF2-HSP110 Axis Promotes Genome Stability by Supporting RNA Polymerase II Dependent Transcription and DNA Repair Gene Expression [CUT&Run]

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A CSB-PAF1 axis activates RNA polymerase II from promoter-proximal sites and restores efficient transcription elongation after DNA damage repair

Project description:The coordinated transcription of genes involves RNA polymerase II enzymes (RNAPII), which pull DNA through their active sites. DNA lesions in transcribed strands block RNAPII elongation and induce a strong transcriptional arrest. The transcription-coupled repair (TCR) pathway ensures the efficient removal of transcription-blocking DNA lesions, but this is not sufficient to overcome this arrest and resume transcription. Through proteomics screens, we find that the TCR-specific CSB protein loads the evolutionary conserved PAF1 complex (PAF1C) onto RNAPII in promoter-proximal regions specifically in response to DNA damage. PAF1C is dispensable for TCR-mediated repair,but is essential to resume RNA synthesis after UV irradiation, suggesting an unexpected uncoupling between DNA repair and transcription restart. Moreover, we find that PAF1C promotes RNAPII pause release in promoter-proximal regions and subsequently acts as a processivity factor that stimulates transcription elongation waves throughout genes. Our findings expose the molecular basis for a non-canonical PAF1C-dependent pathway that restores transcription throughout the human genome after genotoxic stress.

2021-02-28 | PXD016198 | Pride

Analysis of HSF2 target genes using a global promoter ChIP-chip strategy on mouse wild-type testis

Project description:Mapping of in vivo targets for HSF2 by using mammalian tissue material in a global ChIP-chip promoter screen. Chromatin was isolated from three wild-type (WT) mouse testes, crosslinked and sonicated into fragments of 100-500 bp, and the quality of the DNA was controlled before the immunoprecipitation, showing no signs of degradation. The DNA amplified from the HSF2 immunoprecipitation samples was labeled and hybridized against the total input DNA samples, on a 1.5 kb promoter tiling array (NimbleGen Systems Inc.), covering ~26000 promoters of the mouse genome. After hybridization and scanning, HSF2 hybridization signals were Lowess normalized to produce log2 ratios (HSF2 ChIP/Input DNA) for all replicate arrays. The promoter values were calculated as average log2 ratios over all probes for each promoter. To identify the HSF2 target population, we used a non-arbitrary analysis method called RankProd described in Breitling et al. 2004. RankProd has been published as an R/Bioconductor package. Keywords: 1.5 kb mouse promoter ChIP-chip (MM5, NimbleGen Systems Inc.), mouse testis

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Analysis of HSF2 target genes using a global promoter ChIP-chip strategy on mouse wild-type testis

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HSF2 cooperates with HSF1 to drive a transcriptional program critical for the malignant state

Project description:Heat shock factor 1 (HSF1) is well known for its role in the heat shock response (HSR), where it drives a transcriptional program comprising heat shock protein (HSP) genes, and in tumorigenesis, where it drives a program comprising HSPs and many non-canonical target genes that support malignancy. Here, we find that HSF2, an HSF1 paralog with no significant role in the HSR, physically and functionally interacts with HSF1 across diverse types of cancer. HSF1 and HSF2 have strikingly similar chromatin occupancy and regulate a common set of genes which include both HSPs and non-canonical transcriptional targets with roles critical in supporting malignancy. Loss of either HSF1 or HSF2 results in a dysregulated response to nutrient stresses in vitro and reduced tumor progression in cancer cell line xenografts. Taken together, these findings establish HSF2 as a critical cofactor of HSF1 in driving a cancer cell transcriptional program to support the anabolic malignant state.

2022-03-15 | GSE194098 | GEO

Regulation of the RNAPII Pool Is Integral to the DNA Damage Response [TT-seq]

Project description:In response to transcription-blocking DNA damage, cells orchestrate a multi-pronged reaction, involving transcription-coupled DNA repair, degradation of RNAPII and genome-wide transcription shutdown. How these responses are connected has remained unclear. Here we show that damage-induced ubiquitylation of RNAPII itself, at a single lysine (RPB1 K1268), is the focal point for DNA damage response coordination. K1268-ubiquitylation affects DNA repair and signals RNAPII degradation, essential for surviving genotoxic insult. It is also crucial for transcriptional shutdown, in the absence of which cells display dramatic transcriptome alterations. Additionally, regulation of RNAPII stability is central to transcription recovery – indeed, depletion of the RNAPII pool underlies the failure of this process in Cockayne syndrome B cells. These data expose regulation of global RNAPII levels as integral to the cellular DNA damage response, and open the intriguing possibility that RNAPII pool size generally affects cell-specific transcription programmes, in genome instability disorders and even normal cells.

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