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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE241102 | GEO | 2023/08/22

REPOSITORIES: GEO

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Project description:In this study we investigated snRNA-mediated modulation of pre-mRNA splicing across the human transcriptome. We first quantified the relative abundance of snRNAs across a comprehensive range of healthy adult and fetal tissues, revealing a surprising variation in the relative snRNA levels both inter- and intra-tissue. To study the role of snRNAs in cancer-relevant splicing, we used breast cancer as a model, since it exhibits a high rate of aberrant splicing48, but a low frequency of mutations in the splicing machinery52. We observed fluctuations in snRNA adundance across the majority of patients, across all breast cancer subtypes. To investigate the impact of snRNA levels using a controlled system, we knocked down snRNAs in vitro, to analyze splicing both transcriptome-wide and at the level of individual exons and introns. Depletion of each specific snRNA resulted in differential splicing across more than a thousand exon junctions within mRNA transcripts. Knock-down of U1 and U2 levels was primarily associated with changes in exon inclusion rates, whereas U4 and U6 depletion predominantly caused incomplete intron removal and a resulting retention of introns in the mature mRNA. Rather than being driven by a single factor, the observed splicing changes were associated with multiple other splicing-relevant features and mechanisms, including mRNA transcription, intron size, and nucleotide composition. The snRNA-mediated changes to the splicing program were enriched within genes encoding components of core cellular pathways and processes, including multiple aspects of RNA and protein metabolism, and thereby have the potential to impact cell growth and identity. The exons and introns that were sensitive to snRNA levels displayed a high variability in splicing in vivo across primary breast cancer samples, indicating that snRNA dysregulation may contribute to aberrant splicing in cancer. We suggest that the cellular composition of snRNAs constitutes a previously unrecognized layer of splicing regulation within the cell, and that variations or disruptions in the relative abundance of the snRNAs can affect the transcriptome of both healthy and malignant cells.

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

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