From mRNA 3′ processing to genome defense: the CPSF complex in transcription-replication conflict and cancer

Abstract

The Cleavage and Polyadenylation Specificity Factor (CPSF) complex, a core regulator of mRNA 3′-end processing, plays an increasingly recognized role in maintaining genomic stability beyond its canonical function in pre-mRNA cleavage and polyadenylation. By facilitating transcription termination, CPSF ensures timely dissociation of RNA Polymerase II (Pol II) from gene termini, thereby preventing transcriptional readthrough, R-loop (three-stranded RNA: DNA hybrids with displaced single-stranded DNA) accumulation, and transcription-replication conflicts (TRCs)—all of which are potent drivers of DNA double-strand breaks and genomic instability. Dysregulation of CPSF subunits (e.g., CPSF3, CPSF4, CPSF6) has been observed in various cancers, including acute myeloid leukemia, glioblastoma, and hepatocellular carcinoma, where aberrant CPSF function disrupts transcriptional fidelity and exacerbates replication stress. Protein interaction analyses further suggest that CPSF associates with DNA replication and repair factors, such as RPA, BARD1, and PARP1, positioning it at the interface of RNA processing and genome maintenance. Given the transcriptional dependency of cancer cells, CPSF—particularly its catalytic subunit CPSF3—has emerged as a promising therapeutic target, with preclinical studies demonstrating that CPSF3 inhibitors can induce transcriptional stress and synthetic lethality. This review comprehensively summarizes the structural and functional roles of the CPSF complex in cancer biology and targeted therapy, and explores its emerging function as a guardian of genomic stability.

Keywords

CPSF complex / Genomic stability / Transcription termination / R-loops / Transcription-replication conflicts (TRCs) / mRNA 3’ end processing

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Funding

National Natural Science Foundation of China(U24A20740)

Shenzhen Medical Research Fund (D2403014)

RIGHTS & PERMISSIONS

Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare