Back to Search Start Over

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

Authors :
Cui Y
Wang L
Ding Q
Shin J
Cassel J
Liu Q
Salvino JM
Tian B
Source :
Nature communications [Nat Commun] 2023 Aug 01; Vol. 14 (1), pp. 4480. Date of Electronic Publication: 2023 Aug 01.
Publication Year :
2023

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.<br /> (© 2023. The Author(s).)

Details

Language :
English
ISSN :
2041-1723
Volume :
14
Issue :
1
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
37528120
Full Text :
https://doi.org/10.1038/s41467-023-39793-8