Affinage

CPSF1

Cleavage and polyadenylation specificity factor subunit 1 · UniProt Q10570

Round 2 corrected
Length
1443 aa
Mass
160.9 kDa
Annotated
2026-04-28
47 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CPSF1 is the 160 kDa subunit of the cleavage and polyadenylation specificity factor (CPSF) complex and serves as the primary RNA-binding subunit that directly recognizes the AAUAAA hexamer in pre-mRNAs to direct 3'-end cleavage and polyadenylation, while also interacting with CstF-77 and poly(A) polymerase to coordinate the polyadenylation machinery (PMID:1756731, PMID:7590244). CPSF1 is recruited to the transcription preinitiation complex via TFIID and subsequently transfers to the elongating RNA polymerase II CTD, coupling transcription to 3'-end processing (PMID:9002523, PMID:9311784). Beyond canonical polyadenylation, CPSF1 suppresses intergenic poly(A) site usage genome-wide, regulates alternative splicing by competing with spliceosome access at intronic AAUAAA signals, and functions as a CUL4A-dependent E3 ubiquitin ligase targeting HIF-1α and MYC for proteasomal degradation (PMID:39847481, PMID:23151878, PMID:37040401). Heterozygous loss-of-function variants in CPSF1 are associated with early-onset high myopia, and zebrafish cpsf1 loss causes apoptosis of definitive hematopoietic stem cells and abnormal retinal ganglion cell axon projection (PMID:30689892, PMID:21330472).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1991 High

    Identifying which component of the CPSF complex directly contacts the AAUAAA signal was essential for understanding poly(A) site recognition; UV crosslinking and chemical modification experiments established that the 160 kDa subunit (CPSF1) is the RNA-contacting subunit that reads each base of the hexamer.

    Evidence UV crosslinking, gel shift, and chemical modification-exclusion on purified CPSF fractions

    PMID:1756731

    Open questions at the time
    • No structural model of CPSF1-RNA interaction
    • Whether CPSF1 alone is sufficient for full-affinity AAUAAA recognition or requires other subunits
  2. 1995 High

    Cloning CPSF1 and reconstituting its interactions revealed that it independently binds AAUAAA RNA, directly contacts CstF-77 and poly(A) polymerase, and is required for polyadenylation — establishing it as the central scaffold of the 3'-end processing machinery.

    Evidence Recombinant protein binding assays, co-immunoprecipitation, anti-CPSF1 antibody inhibition of in vitro polyadenylation with CPSF rescue

    PMID:7590244

    Open questions at the time
    • Binding domains on CPSF1 responsible for CstF-77 and PAP interaction not mapped
    • Stoichiometry of CPSF1 within the native complex not determined
  3. 1997 High

    How 3'-end processing is coupled to transcription was unclear; two studies demonstrated that CPSF is recruited to the preinitiation complex via TFIID, then transfers to the RNA Pol II CTD during elongation, providing the physical basis for co-transcriptional polyadenylation.

    Evidence CTD affinity chromatography, co-purification of CPSF with Pol II, TFIID immunopurification, dominant-negative TBP overexpression in HeLa cells

    PMID:9002523 PMID:9311784

    Open questions at the time
    • Which CPSF subunit(s) directly contact the CTD vs. TFIID
    • Kinetics of the TFIID-to-CTD handoff in vivo
  4. 2000 Medium

    Demonstrating that CPSF, CstF, and symplekin exist as a pre-assembled holoenzyme in cells established that the polyadenylation machinery is organized as a ready-made complex rather than assembled stepwise on each transcript.

    Evidence Co-immunoprecipitation and co-purification from HeLa cell extracts

    PMID:10669729

    Open questions at the time
    • Whether the holoenzyme is the sole functional form or whether sub-complexes have independent roles
    • Structural organization of the holoenzyme
  5. 2004 High

    Identification of hFip1 as an integral CPSF subunit that forms a ternary complex with CPSF1 and PAP resolved how U-rich elements cooperate with AAUAAA for poly(A) site selection and PAP stimulation.

    Evidence Ternary complex reconstitution from purified proteins, in vitro polyadenylation assays

    PMID:14749727

    Open questions at the time
    • Relative contributions of CPSF1 vs. hFip1 to RNA specificity in vivo
    • Whether hFip1-CPSF1 interaction is regulated
  6. 2011 High

    A zebrafish forward genetic screen revealed that CPSF1 is essential for survival of definitive hematopoietic stem cells, with the molecular mechanism traced to defective polyadenylation of snrnp70, linking CPSF1 transcript-specific activity to a discrete developmental outcome.

    Evidence ENU mutagenesis (grechetto mutant), RT-PCR for snrnp70 polyadenylation, apoptosis assays in caudal hematopoietic tissue

    PMID:21330472

    Open questions at the time
    • Whether snrnp70 is the sole critical CPSF1 target in HSCs or one of many
    • Mammalian validation of this hematopoietic requirement
  7. 2012 High

    CPSF1 was shown to regulate alternative splicing independently of productive cleavage/polyadenylation: its binding to an intronic AAUAAA near the IL7R exon 6 5' splice site competes with spliceosome access, establishing a non-canonical splicing-regulatory function for CPSF1.

    Evidence RNA affinity chromatography/mass spectrometry identification, siRNA knockdown, minigene reporters with AAUAAA mutagenesis

    PMID:23151878

    Open questions at the time
    • Genome-wide scope of CPSF1-mediated splicing regulation via intronic AAUAAA signals
    • Whether other CPSF subunits participate in this splicing competition
  8. 2019 High

    Human genetic and zebrafish functional data demonstrated that CPSF1 haploinsufficiency causes early-onset high myopia and abnormal retinal ganglion cell axon projection, extending CPSF1's in vivo roles to eye development and identifying it as a Mendelian disease gene.

    Evidence Whole-exome sequencing of myopia families, morpholino knockdown with mRNA rescue in zebrafish, RGC axon tracing

    PMID:30689892

    Open questions at the time
    • Specific CPSF1 polyadenylation targets in retinal neurons
    • Whether myopia results from polyadenylation defects, splicing defects, or both
  9. 2022 High

    Two studies established that CPSF1 protein stability is regulated by SIAH1-mediated ubiquitination and degradation, and that CPSF1 directs alternative splicing of the androgen receptor toward the AR-v7 oncogenic variant by binding the AAUAAA in cryptic exon CE3 — revealing a disease-relevant, post-translationally regulated splicing switch.

    Evidence Co-immunoprecipitation (SIAH1-CPSF1), ubiquitination assay, RNA immunoprecipitation for CE3 binding, AR splicing assays in prostate cancer cells

    PMID:35402071

    Open questions at the time
    • Whether SIAH1 regulation of CPSF1 operates in non-cancer contexts
    • Structural basis for CPSF1 recognition of intronic vs. canonical AAUAAA
  10. 2023 High

    A CRISPR screen uncovered an unexpected E3 ubiquitin ligase function for CPSF1: it targets HIF-1α and MYC for CUL4A-dependent proteasomal degradation, and ABL kinases antagonize this by competing for CUL4A binding — establishing CPSF1 as a bifunctional protein linking RNA processing and protein degradation.

    Evidence FACS-based CRISPR/Cas9 screen, co-immunoprecipitation, protein stability assays, competitive CUL4A binding experiments

    PMID:37040401

    Open questions at the time
    • Structural basis for CPSF1's E3 ligase activity and whether it uses a recognizable ubiquitin-ligase domain
    • Full substrate repertoire of CPSF1 E3 activity beyond HIF-1α and MYC
    • Whether E3 ligase and RNA-binding functions are mutually exclusive or concurrent
  11. 2025 High

    Genome-wide poly(A) site profiling after CPSF1 knockdown revealed that it suppresses thousands of intergenic poly(A) sites, preventing 3'UTR lengthening; loss of this suppression reduces mRNA levels of glycolysis genes and inhibits cancer cell growth, connecting CPSF1's core polyadenylation function to metabolic reprogramming.

    Evidence 3'-end sequencing, RNA-seq, glycolysis metabolic assays, growth assays in prostate cancer cells

    PMID:39847481

    Open questions at the time
    • Whether intergenic poly(A) site suppression is CPSF1-specific or shared with other CPSF subunits
    • Mechanism by which 3'UTR lengthening decreases mRNA stability for specific transcripts

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for CPSF1's dual RNA-binding and E3 ubiquitin ligase activities, whether these functions are coordinated or independent, and which CPSF1 polyadenylation targets explain its requirements in hematopoiesis and retinal development.
  • No high-resolution structure of CPSF1 in complex with RNA and/or CUL4A
  • Relationship between E3 ligase activity and canonical polyadenylation function uncharacterized
  • Mammalian genetic models confirming zebrafish phenotypes are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0140098 catalytic activity, acting on RNA 4 GO:0016874 ligase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005654 nucleoplasm 2
Pathway
R-HSA-8953854 Metabolism of RNA 6 R-HSA-1643685 Disease 3 GO:0098772 molecular function regulator activity 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-392499 Metabolism of proteins 1
Complex memberships
CPSF (cleavage and polyadenylation specificity factor)CPSF-CstF-symplekin holoenzyme

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The 160 kDa subunit of CPSF (CPSF1) directly contacts the AAUAAA hexamer signal in pre-mRNA, as demonstrated by UV crosslinking showing a 160 kDa polypeptide covalently linked to the RNA; chemical modification-exclusion experiments confirmed that CPF interacts directly with each base of the AAUAAA signal. UV crosslinking, gel mobility shift assays, chemical modification-exclusion experiments The EMBO journal High 1756731
1995 The 160 kDa subunit of CPSF (CPSF1) was cloned and shown to: (1) bind preferentially to AAUAAA-containing RNAs by itself; (2) interact specifically with CstF-77 (the 77K subunit of cleavage factor CstF); and (3) bind poly(A) polymerase (PAP), providing a mechanistic basis for cooperative CPSF-CstF binding and for CPSF-stimulated poly(A) synthesis. Antibodies against recombinant CPSF1 inhibit polyadenylation in vitro, restored by purified CPSF. cDNA cloning, recombinant protein expression, RNA binding assays, co-immunoprecipitation/pulldown, in vitro polyadenylation inhibition with antibodies Genes & development High 7590244
1997 CPSF specifically binds to the C-terminal domain (CTD) of RNA polymerase II, coupling mRNA 3'-end processing to transcription. CPSF and CstF co-purify with pol II in a high-molecular-mass complex, and CTD truncation inhibits efficient 3'-end processing and transcription termination. CTD affinity chromatography, co-purification, in vivo transcription and processing assays with CTD truncation mutants Nature High 9002523
1997 CPSF is recruited to the transcription preinitiation complex by TFIID (via interaction with TBP-associated factors). After transcription initiation, CPSF dissociates from TFIID and associates with the elongating polymerase. Overexpression of recombinant TBP in HeLa cells reduces polyadenylation efficiency, demonstrating that TFIID-mediated CPSF recruitment is required for efficient 3'-end formation. Immunopurification of TFIID complex, co-purification/co-immunoprecipitation, in vivo overexpression assays in HeLa cells, reporter polyadenylation assays Nature High 9311784
2000 CPSF (including the 160K/CPSF1 subunit), CstF, and symplekin can be isolated from cells as part of a large multiprotein complex, establishing that the mammalian polyadenylation machinery is pre-assembled into a holofactory complex. Immunoprecipitation, co-purification from cell extracts Molecular and cellular biology Medium 10669729
2004 Human Fip1 (hFip1) is an integral subunit of the CPSF complex. hFip1 interacts with PAP and with CPSF160 (CPSF1) to form a ternary complex, and stimulates poly(A) polymerase activity in a U-rich element-dependent manner, identifying a cooperative interaction between hFip1 and CPSF1 in poly(A) site recognition and PAP recruitment. Protein purification, co-immunoprecipitation, in vitro polyadenylation assay, ternary complex reconstitution The EMBO journal High 14749727
2011 In zebrafish, loss-of-function mutation in cpsf1 (grechetto mutant) causes defective polyadenylation of snrnp70 (a gene required for HSC development) and leads to apoptotic death of definitive hematopoietic stem cells (HSCs) in the caudal hematopoietic tissue, resulting in severe depletion of myeloid, erythroid, and lymphoid cells. Primitive hematopoiesis and HSC specification are normal, indicating a specific requirement for cpsf1 in HSC survival and differentiation. ENU mutagenesis screen in zebrafish, genetic mapping, loss-of-function mutation analysis, RT-PCR for polyadenylation of snrnp70, cell counting and apoptosis assays Blood High 21330472
2012 CPSF1 regulates alternative splicing of IL7R exon 6 by binding to an intronic AAUAAA polyadenylation signal downstream of the exon 6 5' splice site. CPSF1 knockdown increases exon 6 inclusion; the effect is independent of productive cleavage/polyadenylation at this site, suggesting that CPSF1 binding to intronic pre-mRNA competes with spliceosome access to the 5' splice site. RNA affinity chromatography followed by mass spectrometry (to identify CPSF1), siRNA knockdown, minigene splicing reporter assays, mutation of AAUAAA signal RNA (New York, N.Y.) High 23151878
2012 CPSF1 was identified as a bona fide mRNA-binding protein in human HeLa cells by UV crosslinking interactome capture, establishing it as an RNA-binding protein that directly contacts mRNA in a cellular context. UV crosslinking followed by oligo(dT) capture and mass spectrometry (interactome capture) Cell Medium 22658674
2019 Heterozygous loss-of-function variants in CPSF1 are associated with early-onset high myopia. Knockdown of cpsf1 by morpholino in zebrafish produces small eyes and abnormal retinal ganglion cell (RGC) axon projection to the tectum; this phenotype is rescued by co-injection of cpsf1 mRNA, demonstrating a role for CPSF1 in RGC axon projection and eye development. Whole-exome sequencing, Sanger sequencing, morpholino knockdown in zebrafish, mRNA rescue experiments, RGC axon tracing Human molecular genetics High 30689892
2020 CPSF1 overexpression in head and neck squamous cell carcinoma (HNSCC) promotes cell proliferation, colony formation, and inhibits apoptosis (validated in cell lines and xenografts). CPSF1 knockdown and overexpression experiments reveal that it broadly regulates alternative splicing events (ASEs) in cancer cells. TCGA data mining, CPSF1 knockdown and overexpression in cell lines, proliferation/colony/apoptosis assays, xenograft models, RNA-seq for ASE identification PloS one Medium 32437477
2020 CPSF1 mediates retinal vascular function through suppression of MAPK/ERK pathway phosphorylation. In a streptozotocin-induced diabetic rat model and high-glucose-treated human retinal vascular endothelial cells (HRVECs), CPSF1 is downregulated; AAV-mediated CPSF1 restoration attenuates retinal histological abnormalities and regulates apoptosis, migration, and vascularization of HRVECs by suppressing MAPK/ERK phosphorylation. STZ-induced diabetic rat model, AAV-CPSF1 administration, high-glucose cell model, Western blotting for ERK phosphorylation, apoptosis/migration/tube formation assays Archives of physiology and biochemistry Medium 32046510
2022 SIAH1 directly interacts with CPSF1 and promotes its ubiquitination and proteasomal degradation. CPSF1, regulated by this E3 ubiquitin ligase, promotes AR splice variant 7 (AR-v7) generation by binding to the AAUAAA polyadenylation signal in the AR cryptic exon CE3, switching the androgen receptor splicing pattern toward the oncogenic AR-v7 isoform. m6A methylation represses SIAH1, thereby stabilizing CPSF1 and promoting AR-v7 in castration-resistant prostate cancer. Microarray analysis, co-immunoprecipitation (SIAH1-CPSF1 interaction), ubiquitination assay, CPSF1 overexpression/knockdown, AR splicing assays, RIP (RNA immunoprecipitation) for CE3 binding, clinical specimen analysis Molecular therapy. Nucleic acids High 35402071
2022 CPSF1 promotes gastric cancer progression by regulating alternative polyadenylation (APA) of NSDHL, shortening its 3'UTR; CPSF1 depletion reduces GC cell proliferation and metastasis. Rescue assays demonstrate that NSDHL mediates the oncogenic effect of CPSF1. RNA-seq for 3'UTR length changes, siRNA knockdown, overexpression, proliferation/invasion assays, rescue experiments with NSDHL re-expression American journal of cancer research Medium 36381317
2023 CPSF1 functions as an E3 ubiquitin ligase that targets HIF-1α and MYC for proteasomal degradation. ABL kinases phosphorylate CUL4A and compete with CPSF1 for CUL4A binding, thereby protecting HIF-1α and MYC from CPSF1-mediated degradation under hypoxia. This was identified via a FACS-based CRISPR/Cas9 screen and validated biochemically. FACS-based CRISPR/Cas9 screen, co-immunoprecipitation, protein stability assays, kinase inhibitor treatment, proteasome inhibition, competitive binding assays between CPSF1 and ABL for CUL4A Proceedings of the National Academy of Sciences of the United States of America High 37040401
2025 CPSF1 knockdown in prostate cancer cells causes widespread usage of intergenic poly(A) sites distal to annotated 3'UTRs, resulting in 3'UTR lengthening and decreased mRNA levels of thousands of genes including key glycolysis genes, and selectively inhibits growth and glycolytic output of prostate cancer cells. siRNA knockdown, global poly(A) site profiling (3'-end sequencing), RNA-seq, metabolic assays (glycolysis measurement), cell growth assays Cell reports High 39847481
2025 HSF1 acts as a transcription factor that binds the promoter region of CPSF1 to regulate its transcription and expression. CPSF1 in turn modulates SREBP1 expression and participates in the AKT/mTOR signaling pathway to influence milk fat and protein synthesis in bovine mammary epithelial cells. Chromatin immunoprecipitation (ChIP) for HSF1 binding to CPSF1 promoter, siRNA knockdown, overexpression, Western blotting for AKT/mTOR/SREBP1 pathway components, milk fat/protein synthesis assays in MAC-T cells Journal of animal science Medium 39932399

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1997 The C-terminal domain of RNA polymerase II couples mRNA processing to transcription. Nature 764 9002523
2002 Comprehensive proteomic analysis of the human spliceosome. Nature 725 12226669
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. Journal of proteome research 422 20020773
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
1997 Transcription factor TFIID recruits factor CPSF for formation of 3' end of mRNA. Nature 267 9311784
2017 A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis. Molecular cell 248 28431233
2013 The functional interactome landscape of the human histone deacetylase family. Molecular systems biology 235 23752268
1995 The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3'-end formation. Genes & development 221 7590244
2004 Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. The EMBO journal 209 14749727
2013 PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Molecular cell 204 24332808
2000 Complex protein interactions within the human polyadenylation machinery identify a novel component. Molecular and cellular biology 200 10669729
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2005 WW domains provide a platform for the assembly of multiprotein networks. Molecular and cellular biology 184 16055720
1991 Cleavage and polyadenylation factor CPF specifically interacts with the pre-mRNA 3' processing signal AAUAAA. The EMBO journal 184 1756731
2013 The protein interaction landscape of the human CMGC kinase group. Cell reports 174 23602568
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2012 Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6. RNA (New York, N.Y.) 37 23151878
2019 CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection. Human molecular genetics 35 30689892
2011 cpsf1 is required for definitive HSC survival in zebrafish. Blood 30 21330472
2001 Overexpression of the CstF-64 and CPSF-160 polyadenylation protein messenger RNAs in mouse male germ cells. Biology of reproduction 28 11369601
2020 Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing. PloS one 17 32437477
2022 m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1. Molecular therapy. Nucleic acids 13 35402071
2020 CPSF1 mediates retinal vascular dysfunction in diabetes mellitus via the MAPK/ERK pathway. Archives of physiology and biochemistry 11 32046510
2023 ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1. Proceedings of the National Academy of Sciences of the United States of America 9 37040401
2021 Mutational screening of AGRN, SLC39A5, SCO2, P4HA2, BSG, ZNF644, and CPSF1 in a Chinese cohort of 103 patients with nonsyndromic high myopia. Molecular vision 7 35002215
2022 CPSF1 positively regulates NSDHL by alternative polyadenylation and promotes gastric cancer progression. American journal of cancer research 5 36381317
2024 Integrated RNA expression and alternative polyadenylation analysis identified CPSF1-CCDC137 oncogenic axis in lung adenocarcinoma. Environmental toxicology 3 38174951
2023 Circ-CPSF1 Worsens Radiation-Induced Oxidative Stress Injury in Caenorhabditis elegans. Biomolecules 2 36671487
2025 CPSF1 inhibition promotes widespread use of intergenic polyadenylation sites and impairs glycolysis in prostate cancer cells. Cell reports 1 39847481
2026 A Homozygous CPSF1 Variant Causes Congenital Cataract, Intellectual Disability and Hyperphagia. Clinical genetics 0 41498167
2025 RETRACTION: Integrated RNA Expression and Alternative Polyadenylation Analysis Identified CPSF1-CCDC137 Oncogenic Axis in Lung Adenocarcinoma. Environmental toxicology 0 39838867
2025 HSF1 and CPSF1 affect milk fat and protein synthesis by regulating the AKT/mTOR signaling pathway. Journal of animal science 0 39932399
2025 CPSF1 Is Co-Amplified with MYC but Is Independently Associated with Alternative Polyadenylation in Cancer. Biology 0 41463412