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

Area of Science:

• Molecular Biology
• RNA Processing
• Biochemistry

Background:

• Cleavage and polyadenylation (CPA) is essential for eukaryotic 3' end RNA processing and transcriptional termination.
• JTE-607 is the first identified inhibitor of CPA in mammalian cells, targeting the CPSF-73 subunit.

Purpose of the Study:

• To investigate the effects of the CPA inhibitor JTE-607 on gene expression and cellular processes.
• To identify factors influencing sensitivity to CPA inhibition.
• To explore the therapeutic potential of CPA inhibitors.

Main Methods:

• Transcriptomic analysis of cells treated with JTE-607.
• Assessing gene expression changes, including transcriptional readthrough and alternative polyadenylation (APA).
• Investigating cellular responses, such as cell cycle progression and synergy with DNA damage repair inhibitors.

Main Results:

• JTE-607 induces both transcriptional readthrough and APA, perturbing gene expression.
• Sensitive genes exhibit a unified transcriptomic signature, similar to PCF11 knockdown.
• Cells with higher CPA activity (e.g., FIP1 overexpression) show greater sensitivity to JTE-607.
• JTE-607 induces S phase crisis and synergizes with DNA damage repair inhibitors.

Conclusions:

• CPA activity and cell proliferation rate are key determinants of CPA inhibitor-mediated cell death.
• CPA inhibitors may hold promise as an adjunct therapy for certain cancers by targeting rapidly proliferating cancer cells.