Elevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation
Abstract Cleavage and polyadenylation (CPA) is responsible for 3′ end processing of eukaryotic poly(A)+ RNAs and preludes transcriptional termination. JTE-607, which targets CPSF-73, is the first known CPA inhibitor (CPAi) in mammalian cells. Here we show that JTE-607 perturbs gene expression throug...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39793-8 |
| _version_ | 1797752730576486400 |
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| author | Yange Cui Luyang Wang Qingbao Ding Jihae Shin Joel Cassel Qin Liu Joseph M. Salvino Bin Tian |
| author_facet | Yange Cui Luyang Wang Qingbao Ding Jihae Shin Joel Cassel Qin Liu Joseph M. Salvino Bin Tian |
| author_sort | Yange Cui |
| collection | DOAJ |
| description | Abstract Cleavage and polyadenylation (CPA) is responsible for 3′ end processing of eukaryotic poly(A)+ RNAs and preludes transcriptional termination. JTE-607, which targets CPSF-73, is the first known CPA inhibitor (CPAi) in mammalian cells. Here we show that JTE-607 perturbs gene expression through both transcriptional readthrough and alternative polyadenylation (APA). Sensitive genes are associated with features similar to those previously identified for PCF11 knockdown, underscoring a unified transcriptomic signature of CPAi. The degree of inhibition of an APA site by JTE-607 correlates with its usage level and, consistently, cells with elevated CPA activities, such as those with induced overexpression of FIP1, display greater transcriptomic disturbances when treated with JTE-607. Moreover, JTE-607 causes S phase crisis and is hence synergistic with inhibitors of DNA damage repair pathways. Together, our data reveal CPA activity and proliferation rate as determinants of CPAi-mediated cell death, raising the possibility of using CPAi as an adjunct therapy to suppress certain cancers. |
| first_indexed | 2024-03-12T17:07:40Z |
| format | Article |
| id | doaj.art-e9b3e1159ab1464199de78e8383a1b46 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T17:07:40Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e9b3e1159ab1464199de78e8383a1b462023-08-06T11:19:20ZengNature PortfolioNature Communications2041-17232023-08-0114112010.1038/s41467-023-39793-8Elevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylationYange Cui0Luyang Wang1Qingbao Ding2Jihae Shin3Joel Cassel4Qin Liu5Joseph M. Salvino6Bin Tian7Gene Expression and Regulation Program, and Center for Systems and Computational Biology, The Wistar InstituteGene Expression and Regulation Program, and Center for Systems and Computational Biology, The Wistar InstituteGene Expression and Regulation Program, and Center for Systems and Computational Biology, The Wistar InstituteDepartment of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical SchoolMolecular and Cellular Oncogenesis Program, The Wistar InstituteMolecular and Cellular Oncogenesis Program, The Wistar InstituteMolecular and Cellular Oncogenesis Program, The Wistar InstituteGene Expression and Regulation Program, and Center for Systems and Computational Biology, The Wistar InstituteAbstract Cleavage and polyadenylation (CPA) is responsible for 3′ end processing of eukaryotic poly(A)+ RNAs and preludes transcriptional termination. JTE-607, which targets CPSF-73, is the first known CPA inhibitor (CPAi) in mammalian cells. Here we show that JTE-607 perturbs gene expression through both transcriptional readthrough and alternative polyadenylation (APA). Sensitive genes are associated with features similar to those previously identified for PCF11 knockdown, underscoring a unified transcriptomic signature of CPAi. The degree of inhibition of an APA site by JTE-607 correlates with its usage level and, consistently, cells with elevated CPA activities, such as those with induced overexpression of FIP1, display greater transcriptomic disturbances when treated with JTE-607. Moreover, JTE-607 causes S phase crisis and is hence synergistic with inhibitors of DNA damage repair pathways. Together, our data reveal CPA activity and proliferation rate as determinants of CPAi-mediated cell death, raising the possibility of using CPAi as an adjunct therapy to suppress certain cancers.https://doi.org/10.1038/s41467-023-39793-8 |
| spellingShingle | Yange Cui Luyang Wang Qingbao Ding Jihae Shin Joel Cassel Qin Liu Joseph M. Salvino Bin Tian Elevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation Nature Communications |
| title | Elevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation |
| title_full | Elevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation |
| title_fullStr | Elevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation |
| title_full_unstemmed | Elevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation |
| title_short | Elevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation |
| title_sort | elevated pre mrna 3 end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation |
| url | https://doi.org/10.1038/s41467-023-39793-8 |
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