CPSF3 (also known as CPSF73) is the endonuclease that cleaves the pre-mRNA downstream from the polyadenylation (PAS) site, which is a prerequisite for polyadenylation (Ryan et al. 2004; Mandel et al. 2006). The identity of the endonuclease of the cleavage and polyadenylation (CPA) complex remained elusive for a long time because of the dependence of the cleavage on many CPA components that recognize the PAS site and sequences upstream and downstream from it (Ryan et al. 2004; Mandel et al. 2006). CPSF3 is a member of the metallo-beta-lactamase family of Zn2+-dependent hydrolases and requires Zn2+ for catalytic activity (Ryan et al. 2004; Mandel et al. 2006), with two Zn2+ ions bound to its active site (Mandel et al. 2006).
XRN2 (5'-3' exoribonuclease 2) was reported as an enzyme involved in degradation of the 3' cleavage fragment, which helps to terminate transcription by RNA Polymerase II (RNA Pol II) in a CPSF3 (also known as CPSF73)- and PP1-dependent manner (Eaton et al. 2018; Eaton et al. 2020).
Changes in relative abundance of a single CPA component can modulate the length of 3' UTRs across the transcriptome by favoring selection of the PAS and thus the cleavage site (Martin et al. 2012). Higher levels of PCF11 and FIP1L1 enhance usage of proximal 3'UTR PASs (Li et al. 2015).
Li, W, You, B, Hoque, M, Zheng, D, Luo, W, Ji, Z, Park, JY, Gunderson, SI, Kalsotra, A, Manley, JL, Tian, B
Martin, G, Gruber, AR, Keller, W, Zavolan, M
Mandel, CR, Kaneko, S, Zhang, H, Gebauer, D, Vethantham, V, Manley, JL, Tong, L
Ryan, K, Calvo, O, Manley, JL
endonuclease activity of Ub-K63-CPA:Spliceosomal A complex (uncleaved pre-mRNA, RNA Pol II Ser2 dephosphorylated) [nucleoplasm]
© 2026 Reactome
