CPSF73

CPSF73 is the catalytic subunit of the cleavage and polyadenylation specificity factor (CPSF) complex, a key player in the 3' end processing of most eukaryotic pre-mRNAs. In humans it is encoded by the CPSF3 gene and is commonly referred to as CPSF-73. The protein functions as the endonuclease that cleaves the nascent transcript downstream of the polyadenylation signal, generating the 3' end that is extended by poly(A) polymerase.

Through interactions with other CPSF components—such as CPSF160, CPSF100, and CPSF30—and with accessory factors like Fip1 and WDR33—the CPSF complex coordinates substrate recognition and catalysis. The cleavage event is coupled to polyadenylation and transcription termination, ensuring proper maturation of most mRNAs.

Structural studies place CPSF73 in the metallo-beta-lactamase superfamily, with an N-terminal metallo-beta-lactamase-like domain and a C-terminal beta-CASP domain. Cleavage requires divalent metal ions (typically Mg2+ or Mn2+) coordinated in the active site, and the enzyme is considered the endonuclease responsible for the site-specific cut.

Evolutionarily conserved, CPSF73 has orthologs in other eukaryotes; in budding yeast the functional equivalent is Ysh1. The protein is essential for viability because proper 3' end processing affects polyadenylation, transcript stability, and gene expression.

Clinical significance: given its essential role, loss or impairment of CPSF73 disrupts mRNA maturation. While specific disease associations are limited, dysregulation of 3' end formation has broad effects on gene expression and remains an area of active research.