Elevated pre-mRNA 3′ end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation

Yange Cui, Luyang Wang, Qingbao Ding, Jihae Shin, Joel Cassel, Qin Liu, Joseph M. Salvino and Bin Tian ()
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Yange Cui: The Wistar Institute
Luyang Wang: The Wistar Institute
Qingbao Ding: The Wistar Institute
Jihae Shin: Rutgers New Jersey Medical School
Joel Cassel: The Wistar Institute
Qin Liu: The Wistar Institute
Joseph M. Salvino: The Wistar Institute
Bin Tian: The Wistar Institute

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39793-8

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