CPSF6

CPSF6 Full Name

cleavage and polyadenylation specific factor 6, 68kDa

CPSF6 Introduction

CPSF6, also known as CFIm68, encodes the 68 kDa subunit of the cleavage factor I (CFIm) complex, a key regulatory component of the pre-mRNA 3′-end processing machinery. Unlike the core CPSF complex that recognizes the AAUAAA polyadenylation signal, CFIm binds to upstream UGUA motif elements and functions as a critical determinant of alternative polyadenylation (APA) site selection. Most eukaryotic pre-mRNAs contain multiple poly(A) signals, and the choice among them governs the length of the 3′ untranslated region (3′ UTR), with far-reaching consequences for mRNA stability, subcellular localization, translational efficiency, and miRNA-mediated regulation. CPSF6 contributes to this decision-making process through its RNA-binding domain, which engages UGUA-containing RNA sequences, and its protein-protein interaction surfaces, which connect CFIm to the broader CPSF and cleavage stimulation factor (CstF) assemblies. Notably, elevated CPSF6 expression promotes systematic usage of distal poly(A) sites, generating longer 3′ UTR isoforms, whereas reduced CPSF6 activity favors proximal site selection and global 3′ UTR shortening.

A landmark study revealed that CPSF6 undergoes liquid-liquid phase separation (LLPS), forming membraneless nuclear condensates that are essential for its APA-regulatory function. Elevated LLPS is associated with preferential usage of distal poly(A) sites and longer 3′ UTRs, while dissolution of CPSF6 condensates shifts APA toward proximal sites. Importantly, the kinase CLK2, which is frequently upregulated in cancers, phosphorylates the arginine/serine-like domain of CPSF6 and disrupts its phase separation, thereby shortening 3′ UTRs of cell-cycle-related genes and accelerating cancer cell proliferation. This mechanism resolves the paradox that CPSF6 expression is often higher in tumors than in normal tissues, yet cancer cells nonetheless display globally shortened 3′ UTRs — it is the phosphorylation-mediated loss of CPSF6 LLPS, not its expression level, that drives the APA switch. Suppression of CPSF6 has further been shown to promote apoptosis in gastric cancer by shortening the VHL 3′ UTR and reducing its tumor-suppressive expression, underscoring the context-dependent oncogenic relevance of CPSF6-mediated APA regulation.

Figure 1. The proposed mechanism of CPSF6 in tumorigenesis of GC progression. (Source: Shi X, et al. 2021)

Alternate Names for CPSF6

CPSF6; cleavage and polyadenylation specific factor 6, 68kDa; cleavage and polyadenylation specific factor 6, 68kD subunit; cleavage and polyadenylation specificity factor subunit 6; CFIM; CFIM68; HPBRII 4; HPBRII 7; protein HPBRII-4/7; CPSF 68 kDa subunit

• 1. Shi X, et al. Suppression of CPSF6 Enhances Apoptosis Through Alternative Polyadenylation-Mediated Shortening of the VHL 3'UTR in Gastric Cancer Cells. Front Genet. 2021 Sep 14;12:707644.
  2. Liu S, et al. CPSF6 regulates alternative polyadenylation and proliferation of cancer cells through phase separation. Cell Rep. 2023 Oct 31;42(10):113197.