CPSF6

Summary

CPSF6 (cleavage and polyadenylation specific factor 6, HGNC:13871) is a protein-coding gene on chromosome 12q15, encoding Cleavage and polyadenylation specificity factor subunit 6 (Q16630). Component of the cleavage factor Im (CFIm) complex that functions as an activator of the pre-mRNA 3’-end cleavage and polyadenylation processing required for the maturation of pre-mRNA into functional mRNAs. It is a common-essential gene (DepMap: required in 90.1% of cancer cell lines).

The protein encoded by this gene is one subunit of a cleavage factor required for 3’ RNA cleavage and polyadenylation processing. The interaction of the protein with the RNA is one of the earliest steps in the assembly of the 3’ end processing complex and facilitates the recruitment of other processing factors. The cleavage factor complex is composed of four polypeptides. This gene encodes the 68kD subunit. It has a domain organization reminiscent of spliceosomal proteins.

Source: NCBI Gene 11052 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 48 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 90.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_007007

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13871
Approved symbol	CPSF6
Name	cleavage and polyadenylation specific factor 6
Location	12q15
Locus type	gene with protein product
Status	Approved
Aliases	CFIM, HPBRII-4, HPBRII-7, CFIM68, CFIM72
Ensembl gene	ENSG00000111605
Ensembl biotype	protein_coding
OMIM	604979
Entrez	11052

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 37 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000266679, ENST00000435070, ENST00000456847, ENST00000547486, ENST00000550075, ENST00000550987, ENST00000551516, ENST00000650046, ENST00000886656, ENST00000886657, ENST00000886658, ENST00000886659, ENST00000886660, ENST00000886661, ENST00000886662, ENST00000886663, ENST00000886664, ENST00000886665, ENST00000886666, ENST00000886667, ENST00000927154, ENST00000927155, ENST00000927156, ENST00000927157, ENST00000927158, ENST00000927159, ENST00000927160, ENST00000927161, ENST00000927162, ENST00000927163, ENST00000927164, ENST00000927165, ENST00000927166, ENST00000927167, ENST00000927168, ENST00000927169, ENST00000941456, ENST00000941457, ENST00000941458, ENST00000941459, ENST00000941460

RefSeq mRNA: 2 — MANE Select: NM_007007 NM_001300947, NM_007007

CCDS: CCDS73494, CCDS8988

Canonical transcript exons

ENST00000435070 — 10 exons

Exon	Start	End
ENSE00000752266	69260044	69260197
ENSE00000752267	69259428	69259543
ENSE00000752269	69258590	69259094
ENSE00000752271	69257732	69257905
ENSE00001392118	69262373	69262562
ENSE00001726541	69269512	69274358
ENSE00001764202	69239569	69239706
ENSE00003557150	69256697	69256842
ENSE00003571977	69251129	69251338
ENSE00003583801	69253051	69253154

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 95.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 64.2456 / max 4716.2916, expressed in 1827 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126652	44.9720	1824
126653	13.5837	1773
126654	5.2199	1481
126671	0.2563	117
126670	0.0926	42
126668	0.0452	12
126669	0.0434	6
206788	0.0325	11

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	95.04	gold quality
bone marrow cell	CL:0002092	94.96	gold quality
calcaneal tendon	UBERON:0003701	94.93	gold quality
ventricular zone	UBERON:0003053	94.89	gold quality
tonsil	UBERON:0002372	94.36	gold quality
adrenal tissue	UBERON:0018303	94.23	gold quality
embryo	UBERON:0000922	94.19	gold quality
left ovary	UBERON:0002119	94.16	gold quality
right ovary	UBERON:0002118	93.69	gold quality
vermiform appendix	UBERON:0001154	93.53	gold quality
sural nerve	UBERON:0015488	93.51	gold quality
endometrium	UBERON:0001295	93.48	gold quality
cortical plate	UBERON:0005343	93.48	gold quality
ovary	UBERON:0000992	93.47	gold quality
islet of Langerhans	UBERON:0000006	93.38	gold quality
tendon	UBERON:0000043	93.27	gold quality
lymph node	UBERON:0000029	92.74	gold quality
caecum	UBERON:0001153	92.57	gold quality
stromal cell of endometrium	CL:0002255	92.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.42	gold quality
bone marrow	UBERON:0002371	92.32	gold quality
palpebral conjunctiva	UBERON:0001812	92.28	gold quality
colonic epithelium	UBERON:0000397	92.16	gold quality
seminal vesicle	UBERON:0000998	92.14	gold quality
body of uterus	UBERON:0009853	92.14	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.09	gold quality
monocyte	CL:0000576	91.98	gold quality
mononuclear cell	CL:0000842	91.88	gold quality
uterus	UBERON:0000995	91.85	gold quality
epithelium of nasopharynx	UBERON:0001951	91.82	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	3.90
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

332 targeting CPSF6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3185	99.99	68.12	1959

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 90.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Data show that cleavage factor I(m) can stimulate both cleavage and poly(adenine) addition, and can act to suppress poly(A) site cleavage in a sequence-dependent manner. (PMID:14690600)
• Elevated levels of human cleavage factor Im suppressed cleavage at the primary poly(A) site of the pre-mRNA encoding the 68 kDa subunit of CFI(m). (PMID:14690600)
• region in the subunit of CF I(m) involved in RNA binding, protein-protein interactions, and subcellular localization (PMID:15169763)
• Key paper demonstrating mechanism of CF Im binding to CPSF. Also challenges the long standing perception of mammalian mRNA 3’-end processing that insists that mammalian poly (A) sites are determined by two sequence elements alone. (PMID:15937220)
• a direct role of the U2AF 65/CF I(m) 59 interaction in the functional coordination of splicing and 3’ end processing. (PMID:17024186)
• CF Im68 subnuclear distribution and mobility (PMID:17267687)
• These results reveal a novel function for the pre-mRNA 3’ end processing factor CF I(m)68 in mRNA export. (PMID:19864460)
• HIV-1 harboring the N74D mutation in capsid protein fails to interact with CPSF6 and evades the nuclear import restriction. (PMID:20227665)
• Data provide evidence that CFIm exists as a heterotetramer of 25-kD, 59-kD and 68-kD subunits of CFIm: CFIm25, CFIm59 and CFIm68. (PMID:20695905)
• Crystal structure of CFIm25-CFIm68 RRM heterotetramer illustrated that CFIm25 homodimer is clamped by two CFIm68 monomers on each side of the dimer interface (PMID:21295486)
• Structure of a CFI(m)25/CFI(m)68 RRM heterotetramer and biochemical data indicated that CFIm25 specifically recognized two UGUA elements, CFIm68 facilitates looping of the intervening RNA. CFIm-mediated RNA looping may regulate alternative polyadenylation (PMID:21295486)
• The study reports the crystal structure of human cleavage factor I(m), comprising cleavage factor I(m)25 and the RNA recognition motif domain of cleavage factor I(m)68 kDa (CF I(m)68RRM). (PMID:21483454)
• A 9-residue stretch of hydrophobic amino acids in CPSF6 restricts HIV-1 infection through an interaction with capsid. (PMID:22301135)
• Knockdown of CF I(m)68 induced a systematic use of proximal polyadenylation sites, indicating that changes in relative abundance of a single 3’ end processing factor can modulate the length of 3’ untranslated regions across the transcriptome. (PMID:22813749)
• CPSF6 binds specifically to a novel proteinprotein interface on the N-terminal domain of HIV-1 capsid protein (CA). (PMID:22956906)
• Loss-of-function of CFIm68 and CFIm25 leads to a transcriptome-wide increase in the use of proximal polyadenylation sites in HEK293 cells. (PMID:23187700)
• TNPO3 promotes HIV-1 infectivity indirectly, by shifting the CA-binding protein CPSF6 to the nucleus, thus preventing the excessive HIV-1 CA stability that would otherwise result from cytoplasmic accumulation of CPSF6. (PMID:23414560)
• These results suggested that inhibition of HIV-1 by TNPO3-depleted cells requires CPSF6. (PMID:23622145)
• A carboxy-terminally truncated human CPSF6 lacking residues encoded by exon 6 inhibits HIV-1 cDNA synthesis and promotes capsid disassembly. (PMID:23658440)
• study uncovers two opposing CA-dependent functions of CPSF6 in HIV-1 replication in vivo; however, the benefit for binding CPSF6 appears to outweigh the cost, providing support for a vital function of CPSF6 during HIV-1 replication in vivo (PMID:24415937)
• NUP153 and CPSF6 have overlapping binding sites, but each makes unique capsid monomers (CA) interactions. Multiple ligands share an overlapping interface in HIV-1 capsid that is lost upon viral disassembly. (PMID:25356722)
• Structural basis of HIV-1 capsid recognition by PF74 and CPSF6. (PMID:25518861)
• integration targeting proceeds via two distinct mechanisms: capsid-CPSF6 binding directs HIV-1 to actively transcribed euchromatin, where the integrase-LEDGF/p75 interaction drives integration into gene bodies. (PMID:26858452)
• CPSF6 binding to its docking site in HIV-1 capsid leads to the recruitment of CFIm tetramer, suggesting that CFIm mediates CPSF6 function(s) in integration site targeting. (PMID:26994143)
• Studies suggest that binding of cleavage factor Im (CFIm) may be one of the earliest steps in promoting formation of an active cleavage complex. (PMID:27528751)
• we found CPSF6 and all core paraspeckles proteins to be overexpressed in human breast cancer cases and their expression to correlate with poor patient outcomes. (PMID:28673861)
• The authors demonstrate that CFIm functions as an enhancer-dependent activator of mRNA 3’ processing. CFIm regulates global alternative polyadenylation by specifically binding and activating enhancer-containing poly(A) sites. (PMID:29276085)
• A novel CPSF6-RARG fusion transcript in acute myeloid leukemia. (PMID:29568099)
• High CPSF6 expression is associated with HIV infections. (PMID:29643241)
• CPSF6-capsid interactions allow the virus to bypass peripheral heterochromatin and penetrate the nuclear structure for integration. (PMID:30173955)
• Study shows that the cellular alternative RNA processing factor CPSF6 plays an important role in the ability of NP1 to suppress internal polyadenylation at (pA)p, in influencing viral mRNA export, and, thus, in modulating gene expression of minute virus of canines, a parvovirus.The cellular RNA processing factor CPSF6 interacted with NP1 in transfected cells and participated with NP1 to modulate its effects. (PMID:30355695)
• nuclear entry of HIV-1 subviral complexes in macrophages is mediated by consecutive binding of Nup153 and CPSF6. (PMID:30672737)
• The crystal structure of the RSLD-TNPO3 complex revealed potential CPSF6 interaction residues, which were confirmed to mediate TNPO3 binding and CPSF6 nuclear import. Both binding and nuclear import were independent of RSLD phosphorylation, though a hyperphosphorylated mimetic mutant failed to bind TNPO3 and mislocalized to the cell cytoplasm (PMID:30916345)
• HIV-1 is more dependent on the K182 capsid residue than HIV-2 for interactions with CPSF6. (PMID:31071616)
• pol II Chromatin immunoprecipitation-quantitative PCR on a subset of protein coding genes after knocking down CFIm68. (PMID:31477156)
• The identification of the direct interaction between viral NP1 and host CPSF6 provides new insights into the mechanism by which a viral small nonstructural protein facilitates the multiple regulation of viral gene expression and replication and reveals a novel target for potent antiviral drug development. (PMID:31666379)
• Largely intact HIV-1 capsids dock at the nuclear pore in infected SupT1-R5 cells, with CPSF6 being a facilitator of nucleoplasmic entry in this cell type. (PMID:31690677)
• The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1. (PMID:31941344)
• Requirement for cleavage factor IIm in the control of alternative polyadenylation in breast cancer cells. (PMID:32295865)
• MxB impedes the NUP358-mediated HIV-1 pre-integration complex nuclear import and viral replication cooperatively with CPSF6. (PMID:32600399)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cpsf6	ENSDARG00000018618
mus_musculus	Cpsf6	ENSMUSG00000055531
rattus_norvegicus	Cpsf6	ENSRNOG00000005927
drosophila_melanogaster	Cpsf6	FBGN0035872
caenorhabditis_elegans		WBGENE00008362

Paralogs (1): CPSF7 (ENSG00000149532)

Protein

Protein identifiers

Cleavage and polyadenylation specificity factor subunit 6 — Q16630 (reviewed: Q16630)

Alternative names: Cleavage and polyadenylation specificity factor 68 kDa subunit, Cleavage factor Im complex 68 kDa subunit, Pre-mRNA cleavage factor Im 68 kDa subunit, Protein HPBRII-4/7

All UniProt accessions (5): Q16630, A0A3B3ISW1, F8VNP8, F8W084, F8WJN3

UniProt curated annotations — full annotation on UniProt →

Function. Component of the cleavage factor Im (CFIm) complex that functions as an activator of the pre-mRNA 3’-end cleavage and polyadenylation processing required for the maturation of pre-mRNA into functional mRNAs. CFIm contributes to the recruitment of multiprotein complexes on specific sequences on the pre-mRNA 3’-end, so called cleavage and polyadenylation signals (pA signals). Most pre-mRNAs contain multiple pA signals, resulting in alternative cleavage and polyadenylation (APA) producing mRNAs with variable 3’-end formation. The CFIm complex acts as a key regulator of cleavage and polyadenylation site choice during APA through its binding to 5’-UGUA-3’ elements localized in the 3’-untranslated region (UTR) for a huge number of pre-mRNAs. CPSF6 enhances NUDT21/CPSF5 binding to 5’-UGUA-3’ elements localized upstream of pA signals and promotes RNA looping, and hence activates directly the mRNA 3’-processing machinery. Plays a role in mRNA export. (Microbial infection) Binds HIV-1 capsid-nucleocapsid (HIV-1 CA-NC) complexes and might thereby promote the integration of the virus in the nucleus of dividing cells (in vitro).

Subunit / interactions. Component of the cleavage factor Im (CFIm) complex which is a heterotetramer composed of two subunits of NUDT21/CPSF5 and two subunits of CPSF6 or CPSF7 or a heterodimer of CPSF6 and CPSF7. The cleavage factor Im (CFIm) complex associates with the CPSF and CSTF complexes to promote the assembly of the core mRNA 3’-processing machinery. Associates with the exon junction complex (EJC). Associates with the 80S ribosome particle. Interacts (via the RRM domain) with NUDT21/CPSF5; this interaction is direct and enhances binding to RNA. Interacts (via Arg/Ser-rich domain) with FIP1L1 (preferentially via unphosphorylated form and Arg/Glu/Asp-rich domain); this interaction mediates, at least in part, the interaction between the CFIm and CPSF complexes and may be inhibited by CPSF6 hyper-phosphorylation. Interacts (via N-terminus) with NXF1; this interaction is direct. Interacts with SRSF3. Interacts with SRSF7. Interacts with SNRNP70. Interacts with TRA2B/SFRS10. Interacts with UPF1. Interacts with UPF3B. Interacts with VIRMA. Interacts (via Arg/Ser-rich domain) with TNPO3; promoting nuclear import of CPSF6 independently of its phosphorylation status. Interacts with YTHDC1. (Microbial infection) Interacts (via C-terminus) with HIV-1 capsid protein p24 (CA).

Subcellular location. Nucleus. Nucleoplasm. Nucleus speckle. Cytoplasm.

Post-translational modifications. Phosphorylated. Phosphorylated in the Arg/Ser-rich domain by SRPK1, in vitro. Symmetrically dimethylated on arginine residues in the GAR motif by PRMT5 in a WDR77- and CLNS1A-dependent manner. Asymmetrically dimethylated on arginine residues in the GAR motif by PRMT1.

Domain organisation. Contains an Arg/Ser-rich domain composed of arginine-serine dipeptide repeats within the C-terminal region that is necessary and sufficient for activating mRNA 3’-processing and alternative polyadenylation (APA).

Similarity. Belongs to the RRM CPSF6/7 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q16630-1	1	yes
Q16630-2	2
Q16630-3	3

RefSeq proteins (2): NP_001287876, NP_008938* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034769	CPSF6_RRM	Domain
IPR034772	CPSF6/7	Family
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR057951	CPSF6/7_RSLD_N	Domain

Pfam: PF00076, PF25524

UniProt features (56 total): region of interest 11, mutagenesis site 11, compositionally biased region 9, modified residue 8, strand 5, helix 4, splice variant 2, turn 2, chain 1, domain 1, short sequence motif 1, sequence conflict 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
4B4N	X-RAY DIFFRACTION	1.81
4U0A	X-RAY DIFFRACTION	2.05
6AY9	X-RAY DIFFRACTION	2.5
4WYM	X-RAY DIFFRACTION	2.6
3P5T	X-RAY DIFFRACTION	2.7
6GX9	X-RAY DIFFRACTION	2.7
4U0B	X-RAY DIFFRACTION	2.8
7SNQ	X-RAY DIFFRACTION	2.81
3P6Y	X-RAY DIFFRACTION	2.9
3Q2S	X-RAY DIFFRACTION	2.9
7ZUD	X-RAY DIFFRACTION	2.93
3Q2T	X-RAY DIFFRACTION	3.06
9CNV	ELECTRON MICROSCOPY	3.16
8GDV	X-RAY DIFFRACTION	3.3
8CL1	ELECTRON MICROSCOPY	3.35
8EJL	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16630-F1	65.11	0.23

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (8): 157, 404, 407, 494, 500, 511, 513, 525

Mutagenesis-validated functional residues (11):

Position	Phenotype
84	reduces affinity for ugua rna by 40%; when associated with a-128.
86	abolishes interaction with nudt21/cpsf5; when associated with v-87.
87	abolishes interaction with nudt21/cpsf5; when associated with v-86.
90–91	reduces affinity for ugua rna by 70%. strongly reduced affinity for ugua rna; when associated with a-94.
94	strongly reduced affinity for ugua rna; when associated with 90-a-a-91.
111	reduces affinity for ugua rna by 85%.
126	increases affinity for ugua rna by 40%.
128	reduces affinity for ugua rna by 40%; when associated with a-84.
202	decreased methylation in presence of prmt5/wdr77. loss of methylation in presence of prmt5/wdr77 or prmt1; when associat
204	decreased methylation in presence of prmt5/wdr77. loss of methylation in presence of prmt5/wdr77 or prmt1; when associat
206	loss of methylation in presence of prmt5/wdr77 or prmt1.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1839117	Signaling by cytosolic FGFR1 fusion mutants
R-HSA-5655302	Signaling by FGFR1 in disease
R-HSA-72187	mRNA 3’-end processing
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-73856	RNA Polymerase II Transcription Termination
R-HSA-77595	Processing of Intronless Pre-mRNAs
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 298 (showing top): AAGCAAT_MIR137, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GNF2_MCM5, GOBP_REGULATION_OF_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, PUJANA_CHEK2_PCC_NETWORK, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_TRANSPORT, GOBP_NUCLEAR_TRANSPORT, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_PROTEIN_HETEROTETRAMERIZATION, GOBP_REGULATION_OF_NUCLEOCYTOPLASMIC_TRANSPORT, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GAZDA_DIAMOND_BLACKFAN_ANEMIA_PROGENITOR_DN, REACTOME_MRNA_3_END_PROCESSING, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA

GO Biological Process (7): mRNA processing (GO:0006397), mRNA 3’-end processing (GO:0031124), positive regulation of RNA export from nucleus (GO:0046833), protein tetramerization (GO:0051262), protein heterotetramerization (GO:0051290), mRNA alternative polyadenylation (GO:0110104), co-transcriptional mRNA 3’-end processing, cleavage and polyadenylation pathway (GO:0180010)

GO Molecular Function (6): RNA binding (GO:0003723), mRNA binding (GO:0003729), ribosomal large subunit binding (GO:0043023), exon-exon junction complex binding (GO:1990448), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), perichromatin fibrils (GO:0005726), cytoplasm (GO:0005737), mRNA cleavage and polyadenylation specificity factor complex (GO:0005847), mRNA cleavage factor complex (GO:0005849), membrane (GO:0016020), nuclear speck (GO:0016607), interchromatin granule (GO:0035061), paraspeckles (GO:0042382), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
FGFR1 mutant receptor activation	1
Signaling by FGFR in disease	1
Processing of Capped Intron-Containing Pre-mRNA	1
Metabolism of RNA	1
RNA Polymerase II Transcription	1
Processing of Capped Intronless Pre-mRNA	1
mRNA 3’-end processing	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
mRNA 3’-end processing	2
binding	2
nuclear ribonucleoprotein granule	2
RNA processing	1
mRNA metabolic process	1
mRNA processing	1
RNA 3’-end processing	1
RNA export from nucleus	1
positive regulation of nucleobase-containing compound transport	1
positive regulation of nucleocytoplasmic transport	1
regulation of RNA export from nucleus	1
protein complex oligomerization	1
protein tetramerization	1
protein heterooligomerization	1
co-transcriptional RNA 3’-end processing, cleavage and polyadenylation pathway	1
nucleic acid binding	1
RNA binding	1
ribosome binding	1
protein-containing complex binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear chromosome	1
chromatin	1
intracellular anatomical structure	1
mRNA cleavage factor complex	1
nuclear protein-containing complex	1
nuclear body	1
protein-containing complex	1

Protein interactions and networks

STRING

2172 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPSF6	NUDT21	O43809	999
CPSF6	U2AF2	P26368	970
CPSF6	VIRMA	Q69YN4	948
CPSF6	YTHDC1	Q96MU7	925
CPSF6	PCF11	O94913	869
CPSF6	SYMPK	Q92797	866
CPSF6	NXF1	Q9UBU9	857
CPSF6	PAPOLG	Q9BWT3	851
CPSF6	PAPOLA	P51003	850
CPSF6	NUP153	P49790	849
CPSF6	PAPOLB	Q9NRJ5	846
CPSF6	CSTF2	P33240	839
CPSF6	CLP1	Q92989	834
CPSF6	CPSF3	Q9UKF6	827
CPSF6	RANBP2	P49792	817

IntAct

193 interactions, top by confidence:

A	B	Type	Score
CPSF6	NUDT21	psi-mi:“MI:0407”(direct interaction)	0.890
CPSF6	NUDT21	psi-mi:“MI:0914”(association)	0.890
NUDT21	CPSF6	psi-mi:“MI:0915”(physical association)	0.890
CPSF6	NUDT21	psi-mi:“MI:0915”(physical association)	0.890
CPSF6	WWP1	psi-mi:“MI:0915”(physical association)	0.780
WWP1	CPSF6	psi-mi:“MI:0915”(physical association)	0.780
SCYL1	SEC31A	psi-mi:“MI:0914”(association)	0.710
ARMC7	CPSF6	psi-mi:“MI:0915”(physical association)	0.670
PPIL1	CPSF6	psi-mi:“MI:0915”(physical association)	0.670
CPSF6	PPIL1	psi-mi:“MI:0915”(physical association)	0.670
CPSF6	ARMC7	psi-mi:“MI:0915”(physical association)	0.670
CPSF6	WWP2	psi-mi:“MI:0915”(physical association)	0.660
FXR2	CSNK2A1	psi-mi:“MI:0914”(association)	0.640
CPSF6	TOLLIP	psi-mi:“MI:0915”(physical association)	0.560
OTUB2	CPSF6	psi-mi:“MI:0915”(physical association)	0.560
TOLLIP	CPSF6	psi-mi:“MI:0915”(physical association)	0.560
CPSF6	OTUB2	psi-mi:“MI:0915”(physical association)	0.560
SRPK2	RRP9	psi-mi:“MI:0914”(association)	0.530
PLSCR1	CPSF6	psi-mi:“MI:0915”(physical association)	0.510
CPSF6	PLSCR1	psi-mi:“MI:0915”(physical association)	0.510
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
NUDT21	HNRNPK	psi-mi:“MI:0914”(association)	0.460

BioGRID (654): CPSF6 (Affinity Capture-MS), PPIL1 (Two-hybrid), TOLLIP (Two-hybrid), OTUB2 (Two-hybrid), ARMC7 (Two-hybrid), CPSF6 (Affinity Capture-MS), CPSF6 (Affinity Capture-MS), CPSF6 (Affinity Capture-MS), CPSF6 (Affinity Capture-MS), CPSF6 (Affinity Capture-MS), CPSF6 (Affinity Capture-MS), CPSF6 (Affinity Capture-MS), CPSF6 (Affinity Capture-MS), CPSF6 (Two-hybrid), GIN1 (Two-hybrid)

ESM2 similar proteins: A1A6K6, B9DFV2, F4HWF9, F4JCU0, F4JP52, F4KDN0, G7ID19, O22812, O80567, O80678, Q08A72, Q0D3J9, Q0P5D2, Q0VBL3, Q10M00, Q16630, Q3MHY8, Q5NVH8, Q5XI29, Q5ZL34, Q6ATR0, Q6DDW4, Q6JB11, Q6NWC6, Q6ZK57, Q7KMJ6, Q7Z5Q1, Q812E0, Q8BTV2, Q8H0P8, Q8LPQ9, Q8N684, Q8W4I9, Q940D0, Q94CJ8, Q96T37, Q9CQT2, Q9LES2, Q9LKA4, Q9LKA5

Diamond homologs: A0A0D1C8Z4, Q0P5D2, Q16630, Q5NVH8, Q5XI29, Q5ZL34, Q6DDW4, Q6NVF9, Q6NWC6, Q8BTV2, Q8N684, Q9VSH4, P10979, Q99070, Q03251, Q9SIX3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CPSF6	“form complex”	“CFI complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 185 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA 3’-end processing	7	10.4×	5e-04
Processing of Capped Intron-Containing Pre-mRNA	15	9.3×	2e-08
mRNA Polyadenylation	14	9.2×	7e-08
mRNA Splicing	11	9.1×	5e-06
mRNA Splicing - Major Pathway	21	8.6×	2e-11
SUMO E3 ligases SUMOylate target proteins	6	8.1×	9e-03
Dengue Virus-Host Interactions	16	5.5×	5e-06
Metabolism of RNA	14	4.4×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	5	23.2×	4e-04
mRNA splicing, via spliceosome	18	10.0×	3e-10
RNA splicing	14	7.5×	4e-06
mRNA processing	14	6.7×	1e-05
protein phosphorylation	13	5.3×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

48 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2163 predictions. Top by Δscore:

Variant	Effect	Δscore
12:69239704:CAGG:C	donor_loss	1.0000
12:69239707:GTAC:G	donor_loss	1.0000
12:69251124:CTCAG:C	acceptor_loss	1.0000
12:69251127:AGG:A	acceptor_loss	1.0000
12:69251128:G:T	acceptor_loss	1.0000
12:69251191:A:AG	acceptor_gain	1.0000
12:69251192:A:G	acceptor_gain	1.0000
12:69251302:A:T	donor_gain	1.0000
12:69251334:CATGG:C	donor_gain	1.0000
12:69251335:ATGG:A	donor_gain	1.0000
12:69251336:TGG:T	donor_gain	1.0000
12:69251337:GG:G	donor_gain	1.0000
12:69251337:GGG:G	donor_gain	1.0000
12:69251337:GGGTA:G	donor_loss	1.0000
12:69251338:GG:G	donor_gain	1.0000
12:69251339:G:GA	donor_loss	1.0000
12:69251339:G:GG	donor_gain	1.0000
12:69253020:A:AG	acceptor_gain	1.0000
12:69253020:AAT:A	acceptor_gain	1.0000
12:69253152:GGG:G	donor_gain	1.0000
12:69253153:GGG:G	donor_gain	1.0000
12:69256838:GAAAA:G	donor_gain	1.0000
12:69256843:G:GG	donor_gain	1.0000
12:69257727:TGCA:T	acceptor_loss	1.0000
12:69257728:GCAG:G	acceptor_loss	1.0000
12:69257729:CA:C	acceptor_loss	1.0000
12:69257730:A:AG	acceptor_gain	1.0000
12:69257731:G:GA	acceptor_gain	1.0000
12:69257731:GCT:G	acceptor_gain	1.0000
12:69257731:GCTA:G	acceptor_gain	1.0000

AlphaMissense

3529 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:69239671:G:C	D9H	1.000
12:69239675:T:G	I10S	1.000
12:69251163:T:C	L32S	1.000
12:69251318:T:G	Y84D	1.000
12:69251322:T:A	I85N	1.000
12:69251324:G:A	G86R	1.000
12:69251324:G:C	G86R	1.000
12:69251325:G:A	G86E	1.000
12:69251325:G:T	G86V	1.000
12:69251331:T:C	L88P	1.000
12:69251331:T:G	L88R	1.000
12:69251336:T:A	W90R	1.000
12:69251336:T:C	W90R	1.000
12:69251338:G:C	W90C	1.000
12:69251338:G:T	W90C	1.000
12:69253051:T:A	W91R	1.000
12:69253051:T:C	W91R	1.000
12:69253053:G:C	W91C	1.000
12:69253053:G:T	W91C	1.000
12:69253070:T:C	L97S	1.000
12:69253120:T:C	F114L	1.000
12:69253121:T:C	F114S	1.000
12:69253122:T:A	F114L	1.000
12:69253122:T:G	F114L	1.000
12:69253126:G:A	E116K	1.000
12:69253127:A:T	E116V	1.000
12:69253131:T:A	N117K	1.000
12:69253131:T:G	N117K	1.000
12:69253140:T:A	N120K	1.000
12:69253140:T:G	N120K	1.000

dbSNP variants (sampled 300 via entrez): RS1000036530 (12:69242320 A>G,T), RS1000088484 (12:69242652 C>G), RS1000199292 (12:69257205 T>C), RS1000206522 (12:69267505 A>C), RS1000241726 (12:69248727 G>A,T), RS1000301788 (12:69253774 A>C,G), RS1000327943 (12:69254306 T>A), RS1000356932 (12:69247696 A>G), RS1000389587 (12:69247973 A>G), RS1000401484 (12:69254630 C>G,T), RS1000626408 (12:69261133 T>C), RS1000758668 (12:69274105 T>G), RS1000839188 (12:69243295 A>T), RS1001012722 (12:69237879 T>C), RS1001041054 (12:69243755 G>A,T)

Disease associations

OMIM: gene MIM:604979 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000175_26	Height	3.000000e-06
GCST002515_1	Pneumoconiosis in silica exposure	2.000000e-08
GCST007327_89	Smoking status (ever vs never smokers)	7.000000e-10
GCST007928_2	Medication use (diuretics)	1.000000e-11
GCST007930_131	Medication use (agents acting on the renin-angiotensin system)	8.000000e-12
GCST008810_82	Smoking initiation (ever regular vs never regular)	2.000000e-09
GCST011703_10	Smoking initiation	2.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior
EFO:0009928	Diuretic use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0005670	smoking initiation

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067065 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.46	Kd	348.6	nM	CHEMBL5653589
6.46	ED50	348.6	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148135: Binding affinity to human CPSF6 incubated for 45 mins by Kinobead based pull down assay	kd	0.3486	uM

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases methylation	9
bisphenol A	affects expression, decreases expression, increases expression	4
sodium arsenite	increases activity, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects localization, increases expression, affects cotreatment, decreases expression	1
decabromobiphenyl ether	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
NSC 689534	affects binding, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Copper	affects binding, decreases expression	1
Demecolcine	decreases expression	1
Diclofenac	affects expression	1
Doxorubicin	affects expression	1
Ethyl Methanesulfonate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651177	Binding	Binding affinity to human CPSF6 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

202 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice