The emerging roles of CFIm25 (NUDT21/CPSF5) in human biology and disease

Abstract

The mammalian cleavage factor I subunit CFIm25 (NUDT21) binds to the UGUA sequences of precursor RNAs. Traditionally, CFIm25 is known to facilitate 3' end formation of pre-mRNAs resulting in the formation of polyadenylated transcripts. Recent studies suggest that CFIm25 may be involved in the cyclization and hence generation of circular RNAs (circRNAs) that contain UGUA motifs. These circRNAs act as competing endogenous RNAs (ceRNAs) that disrupt the ceRNA-miRNA-mRNA axis. Other emerging roles of CFIm25 include regulating both alternative splicing and alternative polyadenylation (APA). APA generates different sized transcripts that may code for different proteins, or more commonly transcripts that code for the same protein but differ in the length and sequence content of their 3' UTRs (3' UTR-APA). CFIm25 mediated global changes in 3' UTR-APA affect human physiology including spermatogenesis and the determination of cell fate. Deregulation of CFIm25 and changes in 3' UTR-APA have been implicated in several human diseases including cancer. In many cancers, CFIm25 acts as a tumor suppressor. However, there are some cancers where CFIm25 has the opposite effect. Alterations in CFIm25-driven 3' UTR-APA may also play a role in neural dysfunction and fibrosis. CFIm25 mediated 3' UTR-APA changes can be used to generate specific signatures that can be used as potential biomarkers in development and disease. Due to the emerging role of CFIm25 as a regulator of the aforementioned RNA processing events, modulation of CFIm25 levels may be a novel viable therapeutic approach. This article is categorized under: RNA Processing > 3' End Processing RNA in Disease and Development > RNA in Disease.

Keywords: CFIm25 (NUDT21); alternative polyadenylation; alternative splicing; cancer; ceRNA.

FIGURE 1.

Cis elements and core proteins involved in 3’end formation. The cis elements found in pre-mRNAs include at a minimum, two UGUA sequences that are each bound by a CFIm25 subunit and the polyadenylation signal AAUAAA which interacts with CPSF30 and WDR33. CstF64 recognizes and binds the GU/G/U rich element. Cleavage is done by the CPSF73 endoribonuclease with optimal cleavage occurring after the CA dinucleotide. Also shown are other members of the 3’end processing complex, CPSF160, CPSF100, hFip1, Pcf11, Clp1, CFIm68, CstF77, CstF50 and symplekin.

FIGURE 2.

Different types of alternative polyadenylation (APA). Splicing APA. Splicing APA also known as alternative terminal exon APA occurs when APA occurs concurrently with splicing. In it’s simplest form, splicing APA involves splicing to different terminal exons. Transcripts with different protein coding regions and different 3’UTRs are generated using different polyadenylation signals (PASs), shown here as PAS1, PAS2 and pPAS3, located on different exons. 3’UTR-APA. In 3’UTR-APA (also known as Tandem/Terminal exon APA) occurs when different PASs located within the same terminal exon are used. The simplest example of 3’UTR-APA is when there is a PAS proximal to the stop codon (pPAS3) and one that is more distal (dPAS4). Usage of either the dPAS or pPAS within the same terminal exon generates transcripts with the same protein coding region but with 3’UTRs of different lengths. The longer 3’UTR contain more binding sites for miRNAs and RNA binding proteins which may be eliminated in the smaller 3’UTR.

FIGURE 3.

Model showing effects of different levels of CFIm25 on 3’UTR-APA. A. Low levels of CFIm25 favor usage of the proximal polyadenylation signal (pPAS) generating transcripts with short 3’UTRs. B. High levels of CFIm25 favor usage of the distal polyadenylation signal (dPAS) resulting in transcripts with long 3’UTRs.

FIGURE 4.

Schematic diagram showing effects of CFIm25 on circRNAs and mRNAs. High levels of CFIm25 facilitate the cyclization of UGUA containing precursor RNAs resulting in circRNA biogenesis. These circRNAs act as molecular sponges for miRNAs redirecting miRNAs from target mRNAs. In the absence of CFIm25, there is reduced circRNAs formation and the miRNAs target mRNAs and reduce translation of target transcripts.