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Showing TBPL1 — TRF2 is a alias.

TBPL1

TATA box-binding protein-like 1 · UniProt P62380

Length
186 aa
Mass
20.9 kDa
Annotated
2026-06-10
41 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBPL1 (TLF/TRF2/TLP) is a TBP-related factor that controls a distinct mode of class II transcription initiation, selectively activating TATA-less promoters while repressing TATA-containing promoters (PMID:12682363, PMID:15767669). Its defining biochemical property is an unusually stable, high-affinity association with TFIIA (Kd ~1.5 nM, with ~18-fold slower dissociation than TBP), and this TFIIA-binding activity both enables activation of TATA-less targets such as TdT and NF1 and underlies repression of TATA promoters such as c-fos by TFIIA sequestration (PMID:14570910, PMID:12682363, PMID:15767669). TFIIA engagement also dictates TBPL1 subcellular behavior: most TBPL1 is cytoplasmic in somatic cells, and TFIIA-binding-defective mutants instead accumulate in the nucleus (PMID:14570910). TBPL1 translocates to the nucleus at G2 phase and after genotoxic stress to act as a p53-independent negative regulator of G2/M progression and the G2 DNA-damage checkpoint (PMID:12773555). At the rDNA intergenic spacer, nucleolar TBPL1 binds TCT motifs to drive both Pol II and Pol I activity, and its loss disrupts nucleolar organization and rRNA biogenesis (PMID:39505901). In vivo, TBPL1 is essential for late spermiogenesis, with knockout causing chromocenter fragmentation, defective acrosome formation, and arrest of round spermatids (PMID:11463376, PMID:11861477). Multiple microRNAs converge on the TBPL1 3'-UTR to restrain its expression in cancer and fibrosis, where TBPL1 supports proliferative and metastatic phenotypes (PMID:24870791, PMID:35122989, PMID:41152284).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Established that TBPL1 has an essential, stage-specific developmental function distinct from the general transcription factor TBP, by showing it is required for a defined step of spermatogenesis.

    Evidence Homologous-recombination knockout in mice with histology and gene expression analysis

    PMID:11463376

    Open questions at the time
    • Direct promoter targets driving the step-7 arrest not defined
    • Did not establish the molecular mechanism linking TBPL1 loss to apoptosis
  2. 2002 High

    Refined the spermatogenic defect to a primary structural cause, linking TBPL1 to heterochromatin organization rather than only gene expression.

    Evidence Analysis of TLF-null mice with HP1 immunofluorescence and chromocenter/acrosome readouts

    PMID:11861477

    Open questions at the time
    • How TBPL1 promotes chromocenter integrity mechanistically is unresolved
    • Connection between heterochromatin role and transcriptional role not bridged
  3. 2003 High

    Defined the central biochemical mechanism — a high-affinity, kinetically stable TBPL1-TFIIA complex — and showed this interaction governs TBPL1's cytoplasmic localization.

    Evidence Surface plasmon resonance kinetics, mutagenesis of TFIIA-binding residues, immunostaining and fractionation in NIH3T3 cells

    PMID:14570910

    Open questions at the time
    • Functional purpose of cytoplasmic sequestration not fully explained
    • Trigger that releases TBPL1 from TFIIA for nuclear entry not identified
  4. 2003 High

    Showed TBPL1 acts as a p53-independent negative regulator of G2/M and a G2 DNA-damage checkpoint factor, coupling its regulated nuclear translocation to cell cycle control.

    Evidence TLP knockout in chicken DT40 cells, flow cytometry, UV/MMS stress challenge, and NLS-TLP overexpression

    PMID:12773555

    Open questions at the time
    • Nuclear targets of TBPL1 during the checkpoint not identified
    • Signal driving rapid stress-induced translocation unknown
  5. 2003 High

    Demonstrated the dual promoter logic of TBPL1 — activation of TATA-less and repression of TATA-containing promoters — and that TFIIA-binding determines which mode dominates.

    Evidence Reporter assays in TLP-null DT40 cells with rescue, TFIIA-binding mutants, and TATA-insertion mutagenesis at the TdT promoter

    PMID:11453637 PMID:12682363

    Open questions at the time
    • Genome-wide promoter repertoire not mapped
    • Whether activation requires additional co-factors beyond TFIIA unclear
  6. 2005 High

    Identified specific natural target genes (NF1 activated, c-fos repressed) and confirmed in vivo relevance, contrasting TBPL1 and TBP as reciprocal regulators acting through TFIIA.

    Evidence EMSA with purified TLF-TFIIA, promoter reporter assays, NF1 mRNA quantification, and TLF-KO mouse analysis

    PMID:15767669

    Open questions at the time
    • Breadth of TATA-less target genes in vivo not defined
    • Sequence determinants of TBPL1 promoter recognition not resolved here
  7. 2014 Medium

    Opened a cancer-relevant regulatory dimension by showing TBPL1 is post-transcriptionally repressed by a microRNA and supports tumor cell proliferation.

    Evidence miR-133b 3'-UTR luciferase reporter, mimic/inhibitor and siRNA experiments, and MTT proliferation assay in colorectal cancer cells

    PMID:24870791

    Open questions at the time
    • Downstream transcriptional program mediating proliferation not defined
    • Single cancer-type context
  8. 2015 Medium

    Reinforced microRNA control of TBPL1 with a second regulator and extended its phenotypic contribution to invasion and migration.

    Evidence miR-18a 3'-UTR luciferase reporter, RT-qPCR, Western blot, MTT, invasion and wound-healing assays in colorectal cancer cells

    PMID:26398009

    Open questions at the time
    • Mechanistic link from TBPL1 to migration/invasion not established
    • No in vivo confirmation
  9. 2022 Medium

    Placed TBPL1 in a defined disease signaling axis (C-MYC -> miR-9-5p -| TBPL1) in pulmonary fibrosis, indicating its expression is tuned by upstream oncogenic transcription factors.

    Evidence ChIP for C-MYC, dual-luciferase reporter for miR-9-5p targeting TBPL1, siRNA/inhibitor studies, and bleomycin mouse model

    PMID:35122989

    Open questions at the time
    • Whether TBPL1's transcriptional activity mediates the fibrotic phenotype not shown
    • Direct TBPL1 target genes in fibroblasts unidentified
  10. 2024 High

    Established a nucleolar function, showing TBPL1 binds TCT motifs at rDNA intergenic spacers to coordinate Pol II and Pol I activity for rRNA biogenesis.

    Evidence Compartment-enriched proximity biotinylation (compBioID), ChIP, RNA-seq, nucleolar fractionation, and depletion phenotyping

    PMID:39505901

    Open questions at the time
    • Mechanism by which TBPL1 couples Pol II to Pol I at IGS not detailed
    • Functional role of PAF1 association with TBPL1 not dissected
  11. 2025 Medium

    Connected TBPL1 to breast cancer biology, showing knockout reshapes transcriptomes governing migration, proliferation and metastasis and that TBPL1 is overexpressed in tumor cells.

    Evidence CRISPR/Cas9 knockout, RNA-seq, and in vivo tumor assay across multiple breast cancer cell lines

    PMID:41152284

    Open questions at the time
    • Direct promoter targets among the altered genes not identified
    • Limited mechanistic depth beyond transcriptome-level association

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TBPL1's transcriptional/TFIIA-sequestering activity, its cell-cycle checkpoint role, its nucleolar rDNA function, and its heterochromatin/spermiogenesis requirement integrate into a unified mechanism remains unresolved.
  • No genome-wide map unifying TBPL1 binding sites across promoters, IGS, and heterochromatin
  • Signal controlling regulated cytoplasm-to-nucleus translocation unknown
  • Mechanistic basis of chromocenter integrity role uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2 GO:0098772 molecular function regulator activity 2 GO:0140223 general transcription initiation factor activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 1 R-HSA-8953854 Metabolism of RNA 1
Partners
GTF2A1PAF1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TLF/TRF2 (TBPL1) is essential for late spermiogenesis in mice; targeted knockout causes complete arrest at step 7 round spermatids with apoptosis, while spermatogonia and spermatocytes develop normally. Several spermiogenesis genes transcribed in late round spermatids require TLF for expression. Homologous recombination knockout in mice, histology, gene expression analysis Molecular cell High 11463376
2002 TLF/TRF2 (TBPL1) is required for heterochromatic chromocenter formation and acrosome formation in early round spermatids; TLF-deficient mice show fragmentation of the chromocenter (the condensed HP1-containing centromeric heterochromatin structure), identified as the likely primary cause of spermatogenic failure. TLF and TBP differ dramatically in temporal expression pattern and intracellular localization. Analysis of TLF-null mice, immunofluorescence for HP1 and chromocenter structure, comparative TBP/TLF localization studies Development (Cambridge, England) High 11861477
2003 TLP/TRF2/TLF (TBPL1) localizes predominantly to the cytoplasm in mammalian cells (NIH3T3); only ~4% of total TLP molecules reside in the nucleus. TLP binds TFIIA with ~7-fold higher affinity (Kd=1.5 nM) than TBP (Kd=10 nM), and the TLP-TFIIA complex dissociates ~18-fold more slowly. TLP forms dimers and trimers that are inhibited by TFIIA. TFIIA-binding ability of TLP (requiring residues Ala-32, Leu-33, Asn-37, Arg-52, Lys-53, Lys-78, Arg-86) is required for its characteristic cytoplasmic localization; TFIIA-binding-defective mutants accumulate in the nucleus. Biophysical binding assays (surface plasmon resonance/kinetics), immunostaining, stable cell lines expressing mutant TLP, subcellular fractionation The Journal of biological chemistry High 14570910
2003 TLP/TRF2/TLF (TBPL1) functions as a negative regulator of the G2/M cell cycle phase; TLP-null chicken DT40 cells show accelerated G2 progression (~20% elevated cell cycle rate). TLP translocates from cytoplasm to nucleus specifically at G2 phase. Ectopic nuclear TLP increases G2/M and apoptotic cell fractions. TLP-null cells have a defective G2 checkpoint response to UV and MMS, and TLP translocates to the nucleus rapidly (within 15 min) after stress. These effects are p53-independent. TLP knockout in chicken DT40 cells, cell cycle analysis by flow cytometry, stress (UV, MMS) challenge, nuclear localization signal (NLS)-TLP overexpression, gene expression analysis Molecular and cellular biology High 12773555
2003 TLP/TRF2/TLF (TBPL1) stimulates transcription from TATA-less promoters (terminal deoxynucleotidyl transferase, TdT) while repressing TATA-containing promoters (adenovirus MLP, E1B). TFIIA-binding ability of TLP is required for activation of TATA-less promoters but suppresses TLP-mediated repression of TATA promoters. TdT promoter activity is lower in TLP-null DT40 cells and rescued by ectopic TLP; insertion of a TATA element abolishes TLP-mediated activation. Transient reporter assays, TLP-null DT40 cells with rescue, TFIIA-binding mutant TLP constructs, promoter insertion mutagenesis Nucleic acids research High 12682363
2001 Artificially promoter-recruited TLP/TLF/TRF2 (TBPL1), fused to Gal4 DNA-binding domain, stimulates basal transcription from both TATA-containing and TATA-less class II promoters in vivo. Stimulation is less TATA-dependent than TBP. Truncation from either terminus or amino acid substitutions at positions equivalent to TBP functional residues abolishes this activity. Gal4-TLP fusion transient transfection reporter assay, deletion and point mutant analysis Biochemical and biophysical research communications Medium 11453637
2005 Human TLF/TRF2 (TBPL1) activates transcription of the NF1 gene by directly binding the NF1 promoter via a TLF-TFIIA complex, and reciprocally inhibits transcription from the TATA-containing c-fos promoter by sequestering TFIIA. TBP acts in the opposite manner: activating c-fos and inhibiting NF1. TLF knockout in mice reduces NF1 mRNA levels, confirming in vivo relevance. Overexpression in cells (NF1 mRNA quantification), in vitro EMSA/binding with purified TLF-TFIIA, promoter reporter assays, TLF KO mouse analysis Molecular and cellular biology High 15767669
2014 miR-133b directly targets the 3'-UTR of TBPL1 mRNA, negatively regulating TBPL1 protein expression in colorectal cancer cells. TBPL1 knockdown reduces proliferation of CRC cells, establishing a functional role for TBPL1 in supporting cancer cell proliferation. Luciferase 3'-UTR reporter assay with wild-type and mutant TBPL1 3'-UTR, miR-133b mimic/inhibitor transfection, siRNA knockdown, Western blotting, MTT proliferation assay Asian Pacific journal of cancer prevention : APJCP Medium 24870791
2015 miR-18a directly targets the 3'-UTR of TBPL1 mRNA to inhibit TBPL1 expression, reducing proliferation, invasion, and migration of colorectal cancer cells. Luciferase 3'-UTR reporter assay, RT-qPCR, Western blotting, MTT assay, cell invasion and wound-healing assay Molecular medicine reports Medium 26398009
2022 C-MYC transcriptionally activates miR-9-5p, which in turn negatively regulates TBPL1 expression; this C-MYC→miR-9-5p⊣TBPL1 axis promotes pulmonary fibroblast proliferation and differentiation, driving idiopathic pulmonary fibrosis. Inhibition of C-MYC restores TBPL1 expression and suppresses fibrosis. ChIP assay (C-MYC binding to miR-9-5p promoter), dual luciferase reporter assay (miR-9-5p targeting TBPL1 3'-UTR), siRNA/inhibitor experiments in cells and bleomycin mouse model, RT-qPCR, Western blot Cellular signalling Medium 35122989
2024 TBPL1 localizes to nucleoli and binds TCT motifs at intergenic spacer (IGS) regions of rDNA, where it drives both RNA Pol II and RNA Pol I activity. TBPL1 deficiency disrupts nucleolar organization and rRNA biogenesis. TBPL1 is part of the nucleolar Pol II interactome alongside PAF1. Compartment-enriched proximity-dependent biotin identification (compBioID), ChIP, RNA-seq, nucleolar fractionation, loss-of-function (TBPL1 depletion) with nucleolar phenotype readout Nature communications High 39505901
2025 TBPL1 knockout in breast cancer cell lines (T47D, SKBR3, MDA-MB-231) via CRISPR/Cas9 alters transcriptome signatures affecting genes involved in cell migration, proliferation, anti-apoptosis, and metastasis. TBPL1 loss also affects cell morphology and growth properties, and TBPL1 is overexpressed in these cancer cell lines relative to normal breast cells. CRISPR/Cas9 knockout, RNA-seq transcriptome profiling, in vivo tumor assay (MDA-MB-231) Scientific reports Medium 41152284

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Late arrest of spermiogenesis and germ cell apoptosis in mice lacking the TBP-like TLF/TRF2 gene. Molecular cell 165 11463376
2002 Distinct functions of TBP and TLF/TRF2 during spermatogenesis: requirement of TLF for heterochromatic chromocenter formation in haploid round spermatids. Development (Cambridge, England) 95 11861477
1986 Equine herpesvirus type 1 (EHV-1) induced abortions and paralysis in a Lipizzaner stud: a contribution to the classification of equine herpesviruses. Archives of virology 60 3015084
2004 Detection of EHV-1 and EHV-4 DNA in unweaned Thoroughbred foals from vaccinated mares on a large stud farm. Equine veterinary journal 47 15163042
2014 MiR-133b acts as a tumor suppressor and negatively regulates TBPL1 in colorectal cancer cells. Asian Pacific journal of cancer prevention : APJCP 41 24870791
2013 A single amino acid substitution in the group 1 Trypanosoma brucei gambiense haptoglobin-hemoglobin receptor abolishes TLF-1 binding. PLoS pathogens 41 23637606
2005 TATA-binding protein (TBP)-like factor (TLF) is a functional regulator of transcription: reciprocal regulation of the neurofibromatosis type 1 and c-fos genes by TLF/TRF2 and TBP. Molecular and cellular biology 39 15767669
2003 TATA-binding protein-like protein (TLP/TRF2/TLF) negatively regulates cell cycle progression and is required for the stress-mediated G(2) checkpoint. Molecular and cellular biology 30 12773555
1985 A possible physiological basis for the dud-stud phenomenon. Hormones and behavior 30 4007800
2003 Specific interaction with transcription factor IIA and localization of the mammalian TATA-binding protein-like protein (TLP/TRF2/TLF). The Journal of biological chemistry 29 14570910
1995 Bovine immunodeficiency virus in stud bull semen. American journal of veterinary research 28 7653885
2022 C-MYC induces idiopathic pulmonary fibrosis via modulation of miR-9-5p-mediated TBPL1. Cellular signalling 25 35122989
2003 Vertebrate TBP-like protein (TLP/TRF2/TLF) stimulates TATA-less terminal deoxynucleotidyl transferase promoters in a transient reporter assay, and TFIIA-binding capacity of TLP is required for this function. Nucleic acids research 23 12682363
2021 The role of estrogen and progesterone receptors in the rotator cuff disease: a retrospective cohort study. BMC musculoskeletal disorders 22 34670550
2008 Use of FAMACHA system to evaluate gastrointestinal nematode resistance/resilience in offspring of stud rams. Veterinary parasitology 18 18314274
2015 Tumor suppressor microRNA-18a regulates tumor proliferation and invasion by targeting TBPL1 in colorectal cancer cells. Molecular medicine reports 16 26398009
1998 Epidemiology of Anoplocephala perfoliata infection in foals on a stud farm in south-western Sweden. Veterinary parasitology 16 9566096
2001 TBP-like protein (TLP/TLF/TRF2) artificially recruited to a promoter stimulates basal transcription in vivo. Biochemical and biophysical research communications 14 11453637
2021 Detection of porcine circovirus type 3 DNA in serum and semen samples of boars from a German boar stud. Veterinary journal (London, England : 1997) 10 34902587
2023 Integrating sperm cell transcriptome and seminal plasma metabolome to analyze the molecular regulatory mechanism of sperm motility in Holstein stud bulls. Journal of animal science 9 37366074
2023 Ablative radiation alone in stage I lung cancer produces an adaptive systemic immune response: insights from a prospective stud. Journal for immunotherapy of cancer 9 37793854
1994 Seroprevalence to Leptospira interrogans serovar hardjo in merino stud rams in South Australia. Australian veterinary journal 9 7945098
2024 Nucleolar Pol II interactome reveals TBPL1, PAF1, and Pol I at intergenic rDNA drive rRNA biogenesis. Nature communications 7 39505901
2023 Characterization of the semen microbiota of healthy stud dogs using 16S RNA sequencing. Theriogenology 7 38141548
2000 Failure to detect bovine immunodeficiency virus contamination of stud bull spermatozoa, blood leukocytes, or semen leukocytes in samples supplied by artificial insemination centers. American journal of veterinary research 7 10895906
1997 [Salinomycin poisoning in a Polish stud horse]. Tierarztliche Praxis. Ausgabe G, Grosstiere/Nutztiere 6 9441047
1998 Fine-mapping of the mouse T lymphocyte fraction (Tlf) locus on chromosome 9: association with autoimmune diabetes. Autoimmunity 5 9754812
2014 Stud male-originating chemosignals: a luteotrophic agent. Indian journal of experimental biology 4 24617011
2010 Efficient identification of novel leads by dynamic focused screening: PDK1 case stud. Combinatorial chemistry & high throughput screening 4 20214573
2021 Survey of anthelmintic resistance in a Romanian horse stud using three different methods. Polish journal of veterinary sciences 3 33847094
2004 [Development of the population size, contribution of foreign breeds, inbreeding and degree of relationships of the entire Hanoverian scenthound population registered in the stud book of the kennel club Hirschmann e.V]. Berliner und Munchener tierarztliche Wochenschrift 3 14964126
1995 Accuracy of predicting genetic merit from pedigree information for bulls entering stud sampling programs. Journal of dairy science 3 8550915
1980 [Estimation of the heritability coefficient of stud fertility]. Veterinarni medicina 3 6773216
2014 A multi-drug resistant HIV-1 protease is resistant to the dimerization inhibitory activity of TLF-PafF. Journal of molecular graphics & modelling 2 25108107
2012 Symptom persistence and memory performance in posttraumatic stress disorder: a gene x environment pilot stud. Behavioral sciences (Basel, Switzerland) 2 25379217
2011 [Association of the DGAT1 gene polymorphism in stud bulls with milk productivity in cows]. Genetika 2 21446190
2025 Ureter reconstruction using a biotube in a canine model: A pilot stud. Journal of stem cells & regenerative medicine 1 41497244
2023 Experimental and Theoretical Study on the Fatigue Crack Propagation in Stud Shear Connectors. Materials (Basel, Switzerland) 1 36676439
2012 Differential plasticity of microglial cells in the rostrocaudal neuraxis of the accessory olfactory bulb of female mice following mating and stud male exposure. Neuroscience letters 1 22405894
2025 RNA-seq analysis of wild-type and mutated TBPL1 gene in breast cancer cells lines through CRISPR/Cas9 approach reveals novel molecular signatures. Scientific reports 0 41152284
1973 Diagnosis of mixed infections with myxovirus influenzae A equi 2 and herpes virus equi 1 among Danish stud horses. Acta veterinaria Scandinavica 0 4353840

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