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CLEAVAGE AND POLYADENYLATION SPECIFICITY FACTOR 6; CPSF6

CLEAVAGE AND POLYADENYLATION SPECIFICITY FACTOR 6; CPSF6

Alternative titles; symbolsPRECURSOR mRNA CLEAVAGE FACTOR Im, 68-KD SUBUNIT; CFIM68HGNC Approved Gene Symbol: CPSF6Cytogenetic location: 12q15 Genomic coordi...

Alternative titles; symbols

  • PRECURSOR mRNA CLEAVAGE FACTOR Im, 68-KD SUBUNIT; CFIM68

HGNC Approved Gene Symbol: CPSF6

Cytogenetic location: 12q15 Genomic coordinates (GRCh38): 12:69,239,567-69,274,357 (from NCBI)

▼ Cloning and Expression
Most eukaryotic mRNA primary transcripts are processed both internally and at their termini in the nucleus, before they are exported to the cytoplasm. Modifications include the generation of a new 3-prime end by endonucleolytic cleavage followed by polyadenylation of the upstream cleavage product. Cleavage factors (CFs) Im and IIm, both of which are required in order for cleavage and polyadenylation to occur, are involved in the first step of 3-prime processing. Three major polypeptides of 25 (604978), 59, and 68 kD and a less abundant polypeptide of 72 kD have been shown to copurify with CF Im (CFIM) activity. Ruegsegger et al. (1998) purified CFIM and obtained peptide sequences from the 25- and 68-kD subunits. By searching sequence databases with the sequences of the 68-kD subunit peptides, they identified a cDNA encoding the 68-kD subunit. The deduced 551-amino acid 68-kD subunit contains 3 distinct domains: an N-terminal RNA-binding domain of the ribonucleoprotein (RNP) type, a proline-rich middle section, and a C-terminal alternating charge domain, which is composed almost exclusively of arginine residues alternating with glutamate and aspartate residues and several serine/arginine dipeptides. This domain organization is strongly reminiscent of that found in SR proteins and SR protein-related polypeptides involved in pre-mRNA splicing. Ruegsegger et al. (1998) demonstrated that CFIM activity can be reconstituted in vitro from only the 25- and 68-kD polypeptides. Several lines of evidence indicated that CFIM exists in at least 2 different forms. Analysis of the kinetics of the cleavage reaction indicated that interaction of CFIM with the RNA is one of the earliest steps in the assembly of the 3-prime end processing complex and facilitates the recruitment of other processing factors.

▼ Gene Structure
Rasaiyaah et al. (2013) showed that HIV-1 capsid mutants N74D and P90A, which are impaired for interaction with cofactors (CPSF6) and cyclophilins (NUP358, 601181 and CYPA, 123840), respectively, cannot replicate in primary human monocyte-derived macrophages because they trigger innate sensors leading to nuclear translocation of NFKB (see 164011) and IRF3 (603734), the production of soluble type I IFN, and induction of an antiviral state. Depletion of CPSF6 with short hairpin RNA expression allowed wildtype virus to trigger innate sensors and IFN production. In each case, suppressed replication was rescued by IFN-receptor blockade, demonstrating a role for IFN in restriction. IFN production is dependent on viral reverse transcription but not integration, indicating that a viral reverse transcription product comprises the HIV-1 pathogen-associated molecular pattern. Finally, Rasaiyaah et al. (2013) demonstrated that they could pharmacologically induce wildtype HIV-1 infection to stimulate IFN secretion and an antiviral state using a nonimmunosuppressive cyclosporine analog. The authors concluded that HIV-1 has evolved to use CPSF6 and cyclophilins to cloak its replication, allowing evasion of innate immune sensors and induction of a cell-autonomous innate immune response in primary human macrophages.

Tags: 12q15