CSTF3: Cleavage Stimulation Factor Subunit 3
A key component of the mRNA polyadenylation machinery, involved in 3' end processing and implicated in cancer and developmental disorders.
Gene Information Card
| Symbol | CSTF3 |
|---|---|
| Full Name | Cleavage Stimulation Factor Subunit 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 11p13 |
| NCBI Gene ID | 1479 ncbi.nlm.nih.gov/gene/1479 |
| Ensembl ID | ENSG00000176102 |
| UniProt ID | Q12996 |
| OMIM ID | 600367 |
| HGNC ID | 2484 |
| Aliases | CPSF3, CSTF3, cleavage stimulation factor 77 kDa subunit |
Description
CSTF3 encodes a 77 kDa subunit of the cleavage stimulation factor (CstF) complex, which is essential for pre-mRNA 3' end processing. The protein binds to the downstream GU-rich element of the polyadenylation signal and interacts with other CstF subunits (CSTF1, CSTF2) and the cleavage and polyadenylation specificity factor (CPSF) to facilitate endonucleolytic cleavage and polyadenylation. Alternative splicing generates multiple transcript variants, and the gene is widely expressed with highest levels in testis and lymphoid tissues.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast cancer | CSTF3 overexpression leads to alternative polyadenylation (APA) of oncogenes, promoting tumorigenesis. | PMID: 25657329; COSMIC |
| Ovarian cancer | Somatic mutations and copy number gains in CSTF3 alter 3' UTR length of target mRNAs, affecting gene expression. | PMID: 28263307; COSMIC |
| Neurodevelopmental disorders | De novo missense variants in CSTF3 are associated with intellectual disability and developmental delay. | PMID: 31036916; ClinVar |
| Acute myeloid leukemia (AML) | CSTF3 fusions (e.g., with RUNX1) disrupt normal polyadenylation, contributing to leukemogenesis. | PMID: 23502222; COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 28.5 | High |
| Lymph node | 22.1 | High |
| Spleen | 19.8 | High |
| Brain | 8.2 | Medium |
| Liver | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 15.3 | Cervical cancer cell line |
| K562 | 12.7 | Leukemia cell line |
| HepG2 | 9.4 | Hepatocellular carcinoma cell line |
| MCF7 | 11.2 | Breast cancer cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1250G>A (p.Arg417Gln) | Missense | 0.001% (gnomAD) | Alters RNA-binding affinity; associated with neurodevelopmental delay (ClinVar) |
| c.1876C>T (p.Arg626Trp) | Missense | 0.0005% (gnomAD) | Impaired CstF complex assembly; reported in AML (COSMIC) |
| c.2140_2141insA (p.Thr714Asnfs*3) | Frameshift | <0.0001% | Loss of function; observed in breast cancer (COSMIC) |
| c.1567G>A (p.Glu523Lys) | Missense | 0.002% (gnomAD) | Alters protein stability; found in ovarian cancer (COSMIC) |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations (e.g., p.Thr714Asnfs*3) truncate the protein, disrupting CstF complex integrity and polyadenylation.
Gain of Function (GOF)
Missense mutations (e.g., p.Arg417Gln) may enhance RNA binding or alter polyadenylation site selection, contributing to oncogenic APA.
Dominant Negative (DN)
Mutations that impair complex assembly (e.g., p.Arg626Trp) can interfere with wild-type CSTF3 function, leading to dominant-negative effects.
View complete mutation data：
Gene Ontology (GO)
| • RNA binding (GO:0003723) | • protein binding (GO:0005515) |
| • mRNA polyadenylation (GO:0006378) | • mRNA 3'-end processing (GO:0031124) |
| • nucleus (GO:0005634) | • mRNA cleavage and polyadenylation specificity factor complex (GO:0005849) |
Pathways
• mRNA 3'-end processing (Reactome: R-HSA-72172)
• Cleavage of Growing Transcript in the Termination Region (Reactome: R-HSA-75205)
• Formation of the CstF complex (Reactome: R-HSA-77075)
Protein Summary
CSTF3 is a 77 kDa nuclear protein that forms a heterotrimeric complex with CSTF1 and CSTF2. It recognizes the GU-rich downstream element of the polyadenylation signal and recruits the CPSF complex to the pre-mRNA. The protein contains an N-terminal proline-rich region, a central RNA-binding domain, and a C-terminal domain involved in protein-protein interactions. Post-translational modifications include phosphorylation, which modulates complex assembly and activity.
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