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- W4384698191 abstract "Gene expression is a highly regulated process that is essential to produce diverse proteins and RNAs required for life. The transfer of genetic information from gene to protein involves many steps including transcription of DNA to pre-mRNA, pre-mRNA processing, mRNA export and translation. Errors in each of these processes can be detrimental. Damage to DNA and transcriptional stress lead to activation of well-characterized transcriptional responses. We investigated the cellular response to inhibitors of pre-mRNA splicing. We hypothesized that pre-mRNA splicing stress, like transcriptional stress, would lead to the activation of a transcriptional response. To induce splicing stress, we used isoginkgetin (IGG), a small molecule inhibitor of spliceosome assembly. We treated HCT116 cells with IGG and completed microarray analysis to identify differentially expressed transcripts induced by IGG. Pathway enrichment analysis identified three enriched pathways, two of which involved the ATF4 transcription factor. ATF4 is a component of integrated stress response (ISR), an adaptive stress response to multiple cellular stresses. We measured multiple characteristics of ISR activation including ATF4 and ATF4 dependent transcript activation and found that IGG activated ATF4 and ATF4 dependent transcripts. We used CRISPR cas9 gene editing to create an ATF4 deficient cell line and completed RNA sequencing (RNA-seq) comparing the transcriptional response of ATF4-deficient and parental cells to IGG, using thapsigargin (Tg) as a positive control for ATF4 activation. We found that the IGG response is almost entirely ATF4-dependent with only 8 of 76 differentially expressed transcripts responding similarly in parental and ATF4-deficient cells while most of the ATF4-dependent transcripts were also responsive to Tg. Transcriptional and splicing stress are known to elicit cell cycle arrests. Therefore, we examined the effect of IGG, and Tg, on the cell cycle in the presence and absence of ATF4. We found that these compounds cause significant, but distinct, alterations in the cell cycle. However, this appeared to be independent of ATF4. This work highlights the central role of ATF4 in the cellular response to IGG but that the ATF4 does not contribute to cell cycle alterations induced by Tg or IGG." @default.
- W4384698191 created "2023-07-20" @default.
- W4384698191 creator A5092494632 @default.
- W4384698191 date "2023-07-18" @default.
- W4384698191 modified "2023-09-25" @default.
- W4384698191 title "Splicing inhibition as a post-transcriptional stress" @default.
- W4384698191 doi "https://doi.org/10.22215/etd/2023-15484" @default.
- W4384698191 hasPublicationYear "2023" @default.
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