Current mechanistic insights into biochemical properties and cellular functions of human Caf1 deadenylases

In eukaryotic cells, mRNA degradation is a critical regulatory step in mRNA metabolism. The removal of poly(A) tail at the 3'-end of mRNA, an initial and rate-limiting step in mRNA degradation termed mRNA deadenylation, is catalyzed by numerous deadenylases. These enzymes are classified into two groups based on their conserved nuclease domains: the DEDD (Asp-Glu-Asp-Asp) superfamily and the EEP (exonuclease-endonuclease-phosphatase) superfamily. Human Caf1 (hCaf1) deadenylases are well-characterized members of the DEDD superfamily, comprising three isoenzymes: hCaf1a/CNOT7, hCaf1b/CNOT8, and hCaf1z/TOE1. Among these, hCaf1a and hCaf1b share high sequence homology, whereas hCaf1z exhibits substantial sequence divergence from the other two, and this divergence contributes to its distinct subcellular localization. Both hCaf1a and hCaf1b are key components of the Ccr4-Not deadenylase complex, and serve as major deadenylases in cytoplasmic mRNA deadenylation and degradation. In contrast, hCaf1z functions in the precise processing of the 3'-end of certain nuclear non-coding RNAs, and plays a crucial role particularly in the processing and maturation of small nuclear RNAs (snRNAs). Despite these extensive studies, the physiological and pathological functions of hCaf1 isoenzymes, as well as their molecular regulatory mechanisms, lack systematic summarization and in-depth investigation, particularly their involvement in tumor progression. Therefore, this review summarizes recent advances in the structural features, subcellular localization, biological functions, and molecular mechanisms of hCaf1 isoenzymes, with a focus on their roles in tumor progression. This work aims to facilitate a comprehensive understanding of hCaf1 family deadenylases.