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CPSF3
CPSF3 Full Name
cleavage and polyadenylation specific factor 3, 73kDa
CPSF3 Introduction
CPSF3, also designated CPSF73, encodes the 73 kDa catalytic subunit of the cleavage and polyadenylation specificity factor (CPSF) complex and serves as the endonuclease that executes the essential cleavage step in eukaryotic pre-mRNA 3′-end processing. CPSF3 belongs to the metallo-β-lactamase superfamily and coordinates zinc ions within its active site to catalyze hydrolysis of the phosphodiester backbone at a defined position downstream of the AAUAAA polyadenylation signal. This endonucleolytic cleavage generates the 3′-OH terminus onto which poly(A) polymerase adds the poly(A) tail — a modification indispensable for mRNA stability, nuclear export, and efficient translation. In addition to its canonical role in polyadenylated mRNA biogenesis, CPSF3 participates in the specialized 3′-end processing of replication-dependent histone mRNAs, which lack poly(A) tails and instead terminate in a stem-loop structure, highlighting the versatility of this enzyme across distinct RNA processing pathways. The dual functionality of CPSF3 in both polyadenylated and histone mRNA maturation makes it indispensable for cell viability and for maintaining the coordinated expression of cell-cycle-regulated genes.
Figure 1. Crystal structures of human CPSF3 in complex with inhibitors. (Source: Tao Y, et al. 2024)
Beyond its fundamental biochemical role, CPSF3 has emerged as a contributor to cancer pathogenesis. In hepatocellular carcinoma, CPSF3 induces cell cycle arrest at the G1-S transition through the PI3K/Akt/GSK-3β signaling pathway, and its elevated expression independently predicts poor prognosis, suggesting a complex role that may differ across tumor types and cellular contexts. In pancreatic cancer, inhibition of CPSF3 disrupts core histone mRNA processing and blocks cell proliferation, while in ovarian cancer, CPSF3-dependent transcription termination has been identified as a potential therapeutic target. Notably, CPSF3 has been classified as a synthetic lethal node in subsets of acute myeloid leukemia and Ewing sarcoma, where tumor cells exhibit heightened dependency on its endonuclease activity compared to normal cells. Biallelic loss-of-function mutations in CPSF3 have also been linked to a neurodevelopmental disorder characterized by microcephaly, hypotonia, nystagmus, and seizures, establishing its essential role in human brain development.
Alternate Names for CPSF3
CPSF3; cleavage and polyadenylation specific factor 3, 73kDa; CPSF73; CPSF-73; cleavage and polyadenylation specificity factor subunit 3; mRNA 3-end-processing endonuclease CPSF-73;
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