Affinage

TPP1

Tripeptidyl-peptidase 1 · UniProt O14773

Length
563 aa
Mass
61.2 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

The TPP1 symbol resolves to two functionally distinct proteins in this corpus: a shelterin component that couples telomere protection to telomerase regulation, and the lysosomal serine protease tripeptidyl-peptidase I (CLN2 gene product). In its dominant, telomere-associated role, TPP1 is the structural hub that tethers the POT1/TPP1 single-stranded DNA-binding heterodimer to the duplex-binding shelterin subcomplex through a direct TIN2 interaction, and this TIN2 bridge is the sole means by which POT1 reaches chromosome ends to protect them (PMID:25056954, PMID:19995905, PMID:16880378). By holding POT1 on the single-stranded telomeric overhang, TPP1 excludes RPA and represses ATR-dependent signaling and a distinct Exo1/BLM resection pathway, thereby maintaining end protection (PMID:22099311, PMID:26778124). Beyond capping, the OB-fold domain of TPP1 directly recruits telomerase to telomeres via association with TERT and stimulates its repeat-addition processivity, functions mediated by the TEL patch and the adjacent NOB surface, which engage the TERT TEN/TRAP region (PMID:23103865, PMID:22863003, PMID:29386102, PMID:35418675, PMID:35201900). Cryo-EM of the telomerase–TPP1(–POT1) complex shows TPP1 forming a structured interface with the TERT TEN domain and TRAP motif that dampens conformational dynamics, while POT1-bound telomeric DNA is stabilized in the active site (PMID:35418675, PMID:35201900). TPP1 thus sets telomere-length homeostasis by providing a distinct telomerase-activation step and by relaying feedback from telomere length (PMID:25128433). Its activity is tuned by post-translational regulation, including Rnf8-mediated K63 ubiquitination that stabilizes its telomeric localization, USP7 deubiquitination controlling its turnover, cell-cycle Ser111 phosphorylation, and Akt-dependent dimerization (PMID:22101936, PMID:25172512, PMID:23509301, PMID:23862686). Germline TEL-patch lesions (notably K170Δ) that abolish telomerase recruitment cause Hoyeraal-Hreidarsson syndrome and bone marrow failure (PMID:25233904, PMID:25205116, PMID:27807141). Separately, the CLN2/TPP1 gene product is a lysosomal serine protease synthesized as an inactive proenzyme that autocatalytically activates at acidic pH using the Ser475 nucleophile with essential Asp360 and Asp517, requires N-glycosylation at Asn286 for activity, and is delivered to lysosomes via the mannose 6-phosphate receptor (PMID:11054422, PMID:14736728, PMID:11415435).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Establishing that the CLN2 gene product is an enzyme answered what biochemical activity the protein carries, defining it as a lysosomal serine protease with a catalytic triad activated under acidic conditions.

    Evidence Recombinant protein purification with pH-dependent activity assays, DFP inhibition stoichiometry, and active-site mutagenesis

    PMID:11054422

    Open questions at the time
    • Endogenous physiological substrate spectrum not defined here
    • Link between enzymatic loss and neurodegeneration not addressed in this study
  2. 2001 High

    Determining how the protease reaches the lysosome and remains active resolved its trafficking route and supported enzyme-replacement feasibility.

    Evidence Recombinant CLN2 from CHO cells with mannose 6-phosphate receptor uptake and activity restoration in LINCL fibroblasts

    PMID:11415435

    Open questions at the time
    • In vivo correction not tested
    • Relationship to the telomere-associated TPP1 not addressed
  3. 2004 Medium

    Identifying N-glycosylation at Asn286 as essential for activity explained how a disease missense mutation inactivates the enzyme without disrupting its sorting.

    Evidence Asn286Ser mutagenesis with deglycosylation and activity assays in HEK293 cells

    PMID:14736728

    Open questions at the time
    • Single expression system
    • Structural basis of glycan-dependent activity not resolved
  4. 2006 High

    Showing that TPP1 (PTOP/PIP1/TINT1) interacts with TIN2 to bridge TRF1 and TRF2 subcomplexes established it as the assembly hub of the six-protein shelterin complex.

    Evidence Reconstitution, reciprocal Co-IP, and shRNA knockdown in human cells

    PMID:16880378

    Open questions at the time
    • Did not address telomerase regulation
    • Structural detail of the TIN2 interface unresolved
  5. 2007 High

    Solving the TPP1 OB-fold structure and reconstituting POT1-TPP1 with telomerase answered whether TPP1 directly modulates the enzyme, defining it as a processivity factor physically linking telomerase to shelterin.

    Evidence X-ray crystallography, in vitro telomerase activity/processivity assays, and OB-fold-dependent Co-IP with cellular loss-of-function (two independent groups)

    PMID:17237767 PMID:17237768

    Open questions at the time
    • Atomic structure of the TPP1-telomerase interface not yet defined
    • Surface residues mediating telomerase contact unmapped
  6. 2008 High

    Characterizing the fission-yeast homolog Tpz1 showed the POT1/TPP1 module is evolutionarily conserved as an effector platform connecting single- and double-stranded telomere domains.

    Evidence Co-IP and genetic deletion/complementation in S. pombe with telomere assays

    PMID:18535244

    Open questions at the time
    • Effector connections (Ccq1/Poz1) not directly mapped to mammalian counterparts
  7. 2009 High

    Conditional TPP1 deletion in mouse cells established that TPP1's primary protective role is to load POT1a/b onto telomeric chromatin, with deletion phenocopying POT1a/b double knockout.

    Evidence Conditional knockout, chromatin fractionation, and epistasis comparison in mouse embryo fibroblasts

    PMID:19995905

    Open questions at the time
    • Did not separate capping from telomerase-recruitment functions
  8. 2010 High

    A cluster of studies dissected how TPP1 recruits and activates telomerase, showing TIN2-tethered TPP1 (OB-fold dependent) recruits the enzyme and that POT1-TPP1 stimulates processivity through a specific TERT contact (TEN-domain G100) rather than a DNA-only effect.

    Evidence FISH/ChIP recruitment assays, shRNA and domain-deletion mutants, in vitro processivity dissection, and TERT point/chimera mutagenesis

    PMID:20094033 PMID:20231318 PMID:20404094 PMID:20493811

    Open questions at the time
    • The exact TPP1 surface contacting TERT not yet pinpointed
    • Mechanism of cell-cycle timing unresolved at this stage
  9. 2011 High

    Defining TIN2's tethering role and Rnf8-mediated K63 ubiquitination clarified how TPP1/POT1 is stabilized on single-stranded DNA to exclude RPA and repress ATR, and how TPP1's telomeric retention is controlled.

    Evidence Conditional TIN2 knockout with RPA/ATR readouts; Co-IP, in vivo ubiquitination, and Rnf8-knockout phenotyping; UPF1 Co-IP with replication analysis

    PMID:21829167 PMID:22099311 PMID:22101936

    Open questions at the time
    • UPF1-TPP1 interaction (Medium) lacks reciprocal structural validation
    • How K63 chains mechanistically anchor TPP1 unresolved
  10. 2012 High

    Identifying the TEL patch and demonstrating OB-fold sufficiency for telomerase recruitment separated TPP1's capping and telomerase functions, defining a single discrete surface that both recruits telomerase and stimulates processivity.

    Evidence OB-fold surface mutagenesis, heterologous-locus tethering, ChIP recruitment, in vitro processivity, and single-molecule FRET of POT1-TPP1 on telomeric DNA

    PMID:22863003 PMID:22981946 PMID:23103865

    Open questions at the time
    • Single-molecule sliding data (Medium) from one lab
    • How TEL patch couples recruitment to catalysis structurally unresolved
  11. 2013 Medium

    Linking Ser111 phosphorylation and Akt-dependent dimerization to telomerase recruitment showed that TPP1 function is cell-cycle and signaling regulated, timing telomerase activity to late S/G2/M.

    Evidence Mass-spec PTM mapping, phospho-specific antibodies and S111 mutagenesis with TRAP assays; Akt inhibition/siRNA with dimerization Co-IP and FISH/ChIP

    PMID:23509301 PMID:23862686

    Open questions at the time
    • Kinase responsible for Ser111 not definitively identified
    • Both findings single-lab
  12. 2014 High

    Disease and genetic-engineering studies established the TEL patch as causally essential, with K170Δ causing Hoyeraal-Hreidarsson syndrome and aplastic anemia by abolishing telomerase recruitment, while TIN2 binding was shown to be the sole route for TPP1/POT1 shelterin association.

    Evidence Exome sequencing with recruitment/processivity assays, family segregation, ZFN-engineered hESC bypass/complementation, and structure-guided TIN2ΔTPP1 knockin epistasis

    PMID:25056954 PMID:25128433 PMID:25205116 PMID:25233904 PMID:25344324 PMID:26778124

    Open questions at the time
    • Feedback set-point mechanism not molecularly defined
    • Distinct resection pathway components only genetically placed
  13. 2014 Medium

    Defining USP7 as a TPP1 deubiquitinase and additional PTM regulators clarified the proteostatic and species-specific control of TPP1 abundance and activity.

    Evidence Co-IP, lysine and interface mutagenesis, ubiquitination and pulse-chase stability assays with proteasome inhibition; Tpz1 SUMOylation site mutagenesis in S. pombe

    PMID:24711392 PMID:25172512

    Open questions at the time
    • USP7 and SUMO findings single-lab
    • Integration of degradation control with telomere cycle unresolved
  14. 2017 High

    Crystal structures of POT1C-TPP1 and the TIN2-TPP1-TRF2 ternary complex provided the architectural basis for shelterin assembly and explained how cancer-associated mutations destabilize the POT1-TPP1 interface.

    Evidence X-ray crystallography with binding assays and telomere length/fragility analysis of cancer mutants

    PMID:28393830 PMID:28393832 PMID:29160297

    Open questions at the time
    • Structures did not capture the TPP1-telomerase interface
  15. 2018 High

    Identifying the NOB region as a second telomerase-interaction surface distinct from the TEL patch refined the model of how TPP1 engages telomerase and confers species specificity.

    Evidence NOB mutagenesis with in vitro processivity, FISH recruitment, and human-mouse swap experiments

    PMID:29386102

    Open questions at the time
    • How NOB and TEL patch jointly dock onto TERT awaited structural definition
  16. 2019 Medium

    Functional dissection of TIN2-stimulated processivity, POT1 ssDNA-length sensing, and TPP1 isoforms refined the regulatory logic of telomerase activation versus inhibition.

    Evidence In vitro processivity with TIN2 isoforms and TEL-patch mutants; hydroxyl-radical footprinting/MS of POT1-TPP1; isoform-specific recruitment/synthesis assays

    PMID:31216472 PMID:31383750 PMID:31685617

    Open questions at the time
    • Each finding single-lab
    • Physiological balance between TPP1-S and TPP1-L in tissues not fully resolved
  17. 2022 High

    Cryo-EM of telomerase bound to TPP1 and TPP1-POT1 delivered the long-sought structural basis of recruitment and activation, showing TPP1 docking on the TERT TEN/TRAP region and POT1-stabilized DNA in the active site.

    Evidence Cryo-EM at 3.2-3.9 Å of telomerase-TPP1(-POT1) complexes (two independent groups)

    PMID:35201900 PMID:35418675

    Open questions at the time
    • Dynamics during repeat addition cycle not fully captured
    • How PTMs reshape this interface unaddressed
  18. 2022 Medium

    Showing that TPP1 promoter variants elevate expression and cooperate with TERT promoter mutations linked TPP1 dosage to telomere lengthening in cancer.

    Evidence Promoter reporter assays and telomere length measurement in melanoma cells

    PMID:36356143

    Open questions at the time
    • Single-lab
    • Causal contribution to tumorigenesis in vivo not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TPP1's two unrelated functions (lysosomal proteolysis and telomere/telomerase regulation) are encoded and regulated within the corpus remains unintegrated, and the dynamic mechanism by which TPP1 hands off telomeric DNA into the telomerase active site during processive synthesis is not fully resolved.
  • No structural snapshot of the catalytic cycle with DNA handoff
  • Integration of cell-cycle PTM control with the cryo-EM interface unresolved
  • Physiological substrate repertoire of the lysosomal protease not mapped in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0003677 DNA binding 4 GO:0060090 molecular adaptor activity 3 GO:0016787 hydrolase activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0000228 nuclear chromosome 5 GO:0005634 nucleus 2 GO:0005764 lysosome 2
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-73894 DNA Repair 2
Partners
POT1RNF8TERTTIN2TRF1TRF2UPF1USP7
Complex memberships
POT1-TPP1 heterodimershelterintelomerase-TPP1 complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Crystal structure of the OB-fold domain of human TPP1 reveals structural similarity to the beta-subunit (TEBP-β) of the ciliate telomere end-binding protein. The POT1-TPP1 complex binds telomeric DNA and increases both the activity and processivity of human telomerase core enzyme, establishing TPP1 as a telomerase processivity factor. X-ray crystallography; in vitro telomerase activity and processivity assays with reconstituted POT1-TPP1-DNA complex Nature High 17237768
2007 TPP1 is a homolog of TEBP-β and its OB fold is required for enhanced POT1 affinity for telomeric ssDNA. TPP1 associates with telomerase in an OB-fold-dependent manner, providing a physical link between telomerase and the shelterin complex. Disruption of POT1-TPP1 interaction causes telomere-length alterations and DNA damage responses. Co-immunoprecipitation; RNAi knockdown; dominant-negative expression; telomere-length and DNA damage assays in human cells Nature High 17237767
2006 TPP1 (then named PTOP/PIP1/TINT1) bridges TRF1 and TRF2 subcomplexes by interacting with TIN2, and is required for assembly of the six-protein shelterin complex. Overexpression of TPP1 enhanced TIN2-TRF2 association; knockdown of TPP1 reduced TRF1-TRF2 complex formation. Reconstitution experiments; co-immunoprecipitation; shRNA knockdown in human cells Proceedings of the National Academy of Sciences of the United States of America High 16880378
2007 Mammalian telomere protection by Pot1 requires its interaction with Tpp1; Tpp1 is essential for the protective function of mammalian Pot1 proteins at chromosome ends. Mouse conditional knockouts with diminished Tpp1; RNAi; complementation with human and mouse Pot1 variants in Pot1 knockout cells Nature structural & molecular biology High 17632522
2008 In fission yeast, Tpz1 (the Tpp1 homolog) forms a complex with Pot1 and recruits effector molecules Ccq1 and Poz1 to protect telomeres and regulate telomerase. Poz1 bridges Pot1-Tpz1 to the Taz1-Rap1 duplex-DNA-binding complex, connecting single-stranded and double-stranded telomeric DNA regions. Co-immunoprecipitation; genetic deletion and complementation in S. pombe; telomere length and protection assays Science High 18535244
2010 TIN2-tethered TPP1 recruits human telomerase to telomeres; depletion of TPP1 or TIN2 (but not POT1) abolishes telomerase recruitment. The OB-fold of TPP1 is required for this recruitment function. Fluorescence in situ hybridization (FISH) and chromatin immunoprecipitation (ChIP) for telomerase at telomeres; shRNA depletion of shelterin subunits; OB-fold deletion mutants Molecular and cellular biology High 20404094
2010 POT1-TPP1 stimulates telomerase processivity by two distinct mechanisms: slowing primer dissociation from telomerase and increasing translocation efficiency. A single POT1-TPP1-DNA interaction is necessary and sufficient for processivity stimulation. In vitro telomerase processivity assays; measurement of primer dissociation rate and translocation efficiency; template-mutant telomerase experiments The EMBO journal High 20094033
2010 POT1-TPP1 stimulation of telomerase processivity requires specific interaction with telomerase (via the TEN domain residue G100 of TERT), not merely a DNA-substrate effect. TPP1 proteins show species-specific interaction with their cognate telomerase. In vitro telomerase activity assays with TERT point mutants (G100); chimeric human-fish telomerases; cross-species POT1-TPP1 combinations Genes & development High 20231318
2010 TPP1 is required for TERT recruitment to telomeres and for telomerase-dependent telomere elongation during nuclear reprogramming. Tpp1-deletion in mouse embryonic fibroblasts causes increased chromosomal instability including sister chromatid fusions and telomere fragility. Conditional Tpp1 deletion in mouse embryonic fibroblasts; TERT ChIP; telomere FISH; nuclear reprogramming to iPSCs Developmental cell High 20493811
2011 TIN2 stabilizes TPP1/POT1a on single-stranded telomeric DNA; upon TIN2 deletion, telomeres lose TPP1/POT1a, accumulate RPA, and activate ATR signaling. The major role of TIN2 is to tether TPP1/POT1a, thereby excluding RPA and repressing ATR. Conditional TIN2 knockout in mouse cells; chromatin fractionation; RPA and ATR signaling assays; epistasis with POT1a/b knockout Molecular cell High 22099311
2011 The E3 ubiquitin ligase Rnf8 physically interacts with Tpp1 and generates Ubc13-dependent Lys63 polyubiquitin chains on Tpp1, stabilizing Tpp1 at telomeres. Rnf8 RING-finger domain is essential for Tpp1 stability and retention. Conserved Tpp1 residue Lys233 is important for Rnf8-mediated ubiquitylation and telomere localization. Co-immunoprecipitation; in vivo ubiquitination assay; site-directed mutagenesis (Lys233); Rnf8 knockout mouse cells with telomere phenotype analysis Nature structural & molecular biology High 22101936
2012 The TEL patch — a specific surface patch of seven amino acids on the OB-fold domain of TPP1 — mediates both telomerase recruitment to telomeres and telomerase processivity stimulation through the same molecular interaction with telomerase. Separation-of-function TEL patch mutants retain full telomere-capping function but are defective in telomerase binding. Site-directed mutagenesis of TPP1 OB-fold surface; in vitro telomerase processivity assays; in vivo telomerase recruitment assays (FISH/ChIP); separation-of-function analysis Nature High 23103865
2012 The OB-fold domain of TPP1 recruits telomerase to telomeres through a direct association with TERT. When tethered away from telomeres, the TPP1 OB-fold is sufficient to recruit telomerase to a heterologous chromatin locus. Specific OB-fold loop residues and individual TERT residues (some mutated in pulmonary fibrosis patients) are required for the TPP1-telomerase interaction. Tethering of TPP1 OB-fold to heterologous chromatin locus; site-directed mutagenesis of TPP1 and TERT; ChIP for telomerase; minimal TPP1 OB-fold dominant-negative expression Cell High 22863003
2012 POT1-TPP1 complex induces continuous folding and unfolding of telomeric G-quadruplex DNA, and slides back and forth on telomeric DNA; POT1 alone cannot recapitulate this sliding activity. Single-molecule fluorescence (FRET) assays; electrophoretic mobility shift assays; comparison of POT1 alone vs. POT1-TPP1 on telomeric substrates Structure Medium 22981946
2009 The primary role of TPP1 in mammalian shelterin is to mediate telomere association of POT1a and POT1b; conditional deletion of TPP1 releases POT1a and POT1b from chromatin. Telomere dysfunction phenotypes from TPP1 deletion are identical to POT1a/POT1b double knockout, establishing that TPP1's main function is to allow POT1 proteins to protect chromosome ends. Conditional TPP1 deletion in mouse embryo fibroblasts; chromatin fractionation; comparison to POT1a/POT1b double KO phenotypes Molecular and cellular biology High 19995905
2000 The CLN2 gene product (TPP1) is a serine protease (tripeptidyl-peptidase I) synthesized as an inactive proenzyme that undergoes autocatalytic activation at acidic pH. The active-site nucleophile is Ser475; Asp360 and Asp517 are also essential for activity. The enzyme is irreversibly inhibited by the serine esterase inhibitor DFP at Ser475. Purification of recombinant protein from insect cells; in vitro enzymatic activity assays at varying pH; DFP inhibition and stoichiometric labeling; site-directed mutagenesis of Ser475, Asp360, Asp517, His236; expression in CHO cells The Journal of biological chemistry High 11054422
2001 Recombinant CLN2/TPP1 protein is secreted as an inactive soluble proenzyme (~65 kDa) that undergoes acidification-induced processing to mature form and acquires enzymatic activity. The enzyme is delivered to lysosomes of LINCL fibroblasts via mannose 6-phosphate receptor-mediated endocytosis (EC50 ~2 nM), where it remains active with a half-life of ~12 days, and restores normal enzyme activity. Production and characterization of recombinant CLN2 from CHO cells; gel filtration; mannose 6-phosphate receptor uptake assays; enzyme activity measurements in LINCL fibroblasts; storage material quantification The Biochemical journal High 11415435
2004 N-glycosylation at Asn286 of CLN2/TPP1 is essential for enzymatic activity; the missense mutation p.Asn286Ser abolishes one oligosaccharide chain and results in enzymatic inactivation, while not affecting sorting to the Golgi. Site-directed mutagenesis (Asn286Ser); transient expression in HEK293 cells; Western blot with deglycosylation; enzyme activity assays; metabolic labeling Glycobiology Medium 14736728
2011 UPF1 physically interacts with TPP1 and with telomerase at telomeres; this interaction is stimulated by ATR kinase. UPF1's ATPase activity is required to prevent telomeric defects, which stem predominantly from inefficient telomere leading-strand replication. Co-immunoprecipitation of UPF1 with TPP1 and telomerase; telomere FISH and replication analysis; UPF1 ATPase-dead mutant complementation; ATR inhibition The EMBO journal Medium 21829167
2013 TPP1 is phosphorylated at multiple sites during cell cycle progression; phosphorylation of Ser111 within the OB fold is important for cell cycle-dependent telomerase recruitment and associates with higher telomerase activity at late S/G2/M. Mutations disrupting Ser111 phosphorylation decrease telomerase activity in the TPP1 complex and cause telomere shortening. Mass spectrometry identification of TPP1 phosphorylation sites; phospho-specific antibodies; S111 mutagenesis; telomerase activity (TRAP) assay; telomere length analysis Proceedings of the National Academy of Sciences of the United States of America Medium 23509301
2014 A germline single-amino-acid deletion in the TEL patch of TPP1 (K170Δ) causes Hoyeraal-Hreidarsson syndrome; this mutation significantly compromises both telomerase recruitment and processivity. A second missense mutation in the TIN2-binding region of TPP1 is not clearly deleterious to TPP1 function. Exome sequencing; telomerase recruitment assay; in vitro telomerase processivity assay; telomere length measurement Genes & development High 25233904
2014 A 1-amino-acid deletion in the TEL patch of TPP1 (ΔK170) in aplastic anemia patients allows TPP1 localization to telomeres but abolishes telomerase recruitment to telomeres, establishing a causal relationship between TEL patch disruption and bone marrow failure. Functional expression of ΔK170 TPP1 in 293T cells; telomerase recruitment assay; telomere length measurement; segregation analysis in family Blood High 25205116
2014 The TPP1 TEL patch is genetically essential for telomere elongation and long-term stem cell viability. TPP1 also provides a distinct essential step of telomerase activation and mediates feedback regulation of telomerase by telomere length to set the telomere length homeostasis set point. Genome engineering (ZFNs) in human embryonic stem cells; genetic bypass assays; intragenic complementation; protein fusion approaches; telomere length measurement Genes & development High 25128433
2014 Binding of TPP1 to TIN2 is the sole mechanism by which TPP1/POT1 heterodimers associate with shelterin and protect telomeres; a TIN2 allele unable to interact with TPP1 but retaining TRF1/TRF2 interactions phenocopies the POT1a/b knockout. Structure-guided mutagenesis to create TIN2ΔTPP1 allele; conditional knockin in mouse cells; telomere dysfunction phenotype comparison The Journal of biological chemistry High 25056954
2014 TPP1 and POT1a/b in shelterin block an ATR-regulated resection pathway distinct from that repressed by TRF2; this second resection pathway involves Exo1 and BLM and is inhibited by 53BP1/Rif1. Conditional knockouts of TPP1, POT1a/b, and TRF2 in mouse cells; Exo1 and BLM deletion epistasis; measurement of 5' end resection at telomeres Molecular cell High 26778124
2014 TRF1 recruits TIN2 and the TPP1/POT1 heterodimers in shelterin to prevent ATR activation during telomere replication; TRF1 separately recruits BLM helicase to facilitate lagging-strand telomeric DNA synthesis. Conditional knockouts of TRF1, BLM, TPP1, and Rap1 in mouse cells; expression of TRF1 and TIN2 mutants; sister telomere association and fragile telomere assays Genes & development High 25344324
2014 USP7 interacts with the OB-fold of TPP1 and deubiquitinates multiple lysine residues within TPP1. TPP1 ubiquitination targets it for proteasomal degradation; prevention of ubiquitination extends TPP1 half-life from ~45 to ~90 min. Co-immunoprecipitation; site-directed mutagenesis of TPP1 lysines and USP7 interaction interface; ubiquitination assays; pulse-chase protein stability measurements; proteasome inhibition The Journal of biological chemistry Medium 25172512
2017 Crystal structure of POT1C (C-terminal OB-fold + Holliday junction resolvase-like domain) complexed with the POT1-binding motif of TPP1, revealing an elongated V-shaped architecture. Both domains of POT1C are essential for TPP1 binding. Cancer-associated mutations partially disrupt the POT1-TPP1 complex, impairing telomeric DNA binding and leading to longer, fragile telomeres. X-ray crystallography; biochemical binding assays with cancer mutants; telomere length and fragility analysis Nature communications High 28393830 28393832
2017 Crystal structure of TIN2 N-terminal domain in complex with TIN2-binding motifs from both TPP1 and TRF2 reveals that TIN2 contains a TRFH-like domain and interacts cooperatively with TPP1 and TRF2. Structure-based mutagenesis shows TIN2 maintains stable shelterin assembly required for telomere end protection. X-ray crystallography of TIN2-TPP1-TRF2 ternary complex; structure-based mutagenesis; telomere protection functional assays Cell research High 29160297
2018 The N-terminal region of the OB domain of TPP1 (NOB region) is critical for telomerase repeat addition processivity in vitro and for telomerase recruitment and telomere lengthening in cells. NOB and TEL patch are distinct but both required surfaces on TPP1 for telomerase interaction, and NOB determines species specificity. Site-directed mutagenesis of TPP1 NOB residues; in vitro telomerase processivity assays; telomerase recruitment (FISH); telomere length measurement; human-mouse NOB swap experiments Cell reports High 29386102
2013 Akt kinase regulates TPP1 homodimerization through the OB-fold; Akt inhibition reduces TPP1 dimerization and diminishes recruitment of TPP1 and POT1 to telomeres, causing telomere dysfunction. Chemical inhibitors and siRNA against Akt; co-immunoprecipitation for TPP1 homodimerization; telomere FISH; chromatin immunoprecipitation Aging cell Medium 23862686
2014 SUMOylation of the fission yeast TPP1 homolog Tpz1 at Lys242 promotes recruitment of Stn1-Ten1 to telomeres, thereby preventing telomerase accumulation at telomeres and negatively regulating telomere length. Site-directed mutagenesis of SUMO acceptor site (K242); genetic analysis; telomerase association assays; Stn1 recruitment assays in S. pombe Proceedings of the National Academy of Sciences of the United States of America Medium 24711392
2016 The K170Δ disease mutation in the TEL patch of TPP1 deforms the conformation of two critical TEL patch amino acids as revealed by X-ray crystallography. Introduction of this mutation in heterozygous form via CRISPR-Cas9 shortens telomeres in human cells, indicating that reduced TEL patch dosage (not dominant-negative effects) causes telomere shortening. X-ray crystallography of K170Δ TPP1; CRISPR-Cas9 heterozygous knock-in in human cells; telomere length measurement Proceedings of the National Academy of Sciences of the United States of America High 27807141
2019 TIN2 stimulates telomerase processivity in vitro through the TPP1/POT1 complex; mutations in the TPP1 TEL patch abrogate TIN2-mediated processivity stimulation, establishing TIN2/TPP1/POT1 as a functional shelterin subcomplex for telomerase regulation. In vitro telomerase processivity assays with TIN2 isoforms; TEL patch mutant analysis; telomere integrity assays in cells Molecular and cellular biology Medium 31383750
2019 POT1 His266 regulates POT1-TPP1 binding to short telomeric ssDNA, and multiple native POT1-TPP1 complexes coating physiologically long ssDNA inhibit telomerase; the CLL-associated POT1 H266L mutation abrogates this telomerase inhibitory function, leading to telomere overextension. Hydroxyl radical footprinting coupled to mass spectrometry; equilibrium binding assays; in vitro telomerase assays; cellular telomere length analysis Proceedings of the National Academy of Sciences of the United States of America Medium 31685617
2019 Two separation-of-function isoforms of TPP1 (TPP1-L and TPP1-S, differing by 86 N-terminal amino acids) have distinct roles: both recruit telomerase, but only TPP1-S efficiently facilitates telomere synthesis. TPP1-S predominates in somatic cells and TPP1-L is the major isoform in differentiated male germ cells where it may restrain telomerase. Identification of isoforms from separate transcripts; ectopic expression of each isoform; in vitro telomerase processivity assays; telomerase recruitment assays; immunofluorescence in germ cells Cell reports Medium 31216472
2022 Cryo-EM structure of human telomerase in complex with TPP1 reveals that TPP1 forms a structured interface with the TERT TEN domain and TRAP motif. TPP1 binding dampens conformational dynamics of TEN-TRAP, defining the structural basis of telomerase recruitment and activation. The TPP1 binding site on TERT overlaps with the binding site of the telomerase inhibitor BIBR1532. Cryo-electron microscopy at 3.x Å resolution; structural comparison of telomerase with and without TPP1; identification of TEN-TRAP interface Nature High 35418675
2022 Cryo-EM structures of telomerase in complex with TPP1 and with TPP1-POT1 at 3.2 and 3.9 Å resolution define the interactions crucial for telomerase recruitment. TPP1-POT1 stabilizes the telomeric DNA in the active site, revealing an unexpected DNA exit path and a DNA anchor site on telomerase important for processivity. Cryo-electron microscopy at 3.2–3.9 Å resolution of telomerase-TPP1 and telomerase-TPP1-POT1 complexes Science High 35201900
2022 TPP1 promoter variants in melanoma create or modify ETS transcription factor binding sites, increase TPP1 expression, and synergistically lengthen telomeres when combined with TERT promoter mutations, demonstrating that elevated TPP1 expression cooperates with TERT to enhance telomere maintenance. Identification of somatic promoter variants; reporter assays for promoter activity; telomere length measurement in melanoma cells with variant combinations Science Medium 36356143
2015 Specific residues in the hTERT insertion in fingers domain (IFD) mediate telomerase processivity and recruitment to telomeres in a TPP1-dependent manner; hTERT-L805A shows impaired telomere association that is partially rescued by TPP1-POT1 overexpression. Site-directed mutagenesis of hTERT IFD; in vitro telomerase activity and processivity assays; telomerase localization assays; TPP1-POT1 overexpression rescue Molecular and cellular biology Medium 26503784

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature 561 17237768
2007 TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature 390 17237767
2018 Study of Intraventricular Cerliponase Alfa for CLN2 Disease. The New England journal of medicine 352 29688815
1990 Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2. Cell 348 2147873
2012 The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 284 23103865
2012 TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell 237 22863003
2006 A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proceedings of the National Academy of Sciences of the United States of America 197 16880378
2010 TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Molecular and cellular biology 194 20404094
1991 FUS3 represses CLN1 and CLN2 and in concert with KSS1 promotes signal transduction. Proceedings of the National Academy of Sciences of the United States of America 192 1946350
2011 Telomere protection by TPP1/POT1 requires tethering to TIN2. Molecular cell 189 22099311
2008 Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length. Science (New York, N.Y.) 186 18535244
2014 TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling. Genes & development 156 25344324
2007 Telomere protection by mammalian Pot1 requires interaction with Tpp1. Nature structural & molecular biology 152 17632522
1993 Yeast G1 cyclins CLN1 and CLN2 and a GAP-like protein have a role in bud formation. The EMBO journal 151 8262070
2010 POT1-TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. The EMBO journal 144 20094033
1997 Rad53-dependent phosphorylation of Swi6 and down-regulation of CLN1 and CLN2 transcription occur in response to DNA damage in Saccharomyces cerevisiae. Genes & development 125 9367985
2019 TPP1 Delivery to Lysosomes with Extracellular Vesicles and their Enhanced Brain Distribution in the Animal Model of Batten Disease. Advanced healthcare materials 120 30997751
2010 TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice. Developmental cell 116 20493811
2013 Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway. Human molecular genetics 112 24271013
2000 The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH. The Journal of biological chemistry 112 11054422
2015 AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease. Science translational medicine 111 26560358
2012 POT1-TPP1 regulates telomeric overhang structural dynamics. Structure (London, England : 1993) 108 22981946
1994 G1 cyclins CLN1 and CLN2 repress the mating factor response pathway at Start in the yeast cell cycle. Genes & development 107 7926787
2006 A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Molecular genetics and metabolism 105 16621647
2010 Functional interaction between telomere protein TPP1 and telomerase. Genes & development 101 20231318
2014 Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes & development 98 25233904
2009 Telomere protection by TPP1 is mediated by POT1a and POT1b. Molecular and cellular biology 97 19995905
2014 Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1. Blood 92 25205116
2014 Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes & development 91 25128433
2017 Structural and functional analysis of the human POT1-TPP1 telomeric complex. Nature communications 86 28393830
2022 Structure of active human telomerase with telomere shelterin protein TPP1. Nature 84 35418675
2017 Management Strategies for CLN2 Disease. Pediatric neurology 82 28335910
2017 Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nature communications 82 28393832
2022 Structural basis of human telomerase recruitment by TPP1-POT1. Science (New York, N.Y.) 80 35201900
2017 Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. Cell research 74 29160297
2011 Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication. The EMBO journal 74 21829167
2014 TRF2-tethered TIN2 can mediate telomere protection by TPP1/POT1. Molecular and cellular biology 68 24469404
2001 Production and characterization of recombinant human CLN2 protein for enzyme-replacement therapy in late infantile neuronal ceroid lipofuscinosis. The Biochemical journal 66 11415435
1994 Cell cycle-dependent transcription of CLN2 is conferred by multiple distinct cis-acting regulatory elements. Molecular and cellular biology 65 8007978
2005 AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL. Gene therapy 64 16052206
2013 Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease). Human mutation 62 23418007
2011 The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection. Nature structural & molecular biology 61 22101936
1998 Structural organization and sequence of CLN2, the defective gene in classical late infantile neuronal ceroid lipofuscinosis. Genomics 56 9653647
2002 Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons. Annals of neurology 54 11921051
2016 TPP1 Blocks an ATR-Mediated Resection Mechanism at Telomeres. Molecular cell 53 26778124
2013 Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment. Proceedings of the National Academy of Sciences of the United States of America 53 23509301
1994 Role of Swi4 in cell cycle regulation of CLN2 expression. Molecular and cellular biology 53 8007977
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2013 A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation. Brain : a journal of neurology 50 23587805
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1999 Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. Human mutation 50 10477428
2014 Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis. Molecular genetics and metabolism 49 25257657
1998 Potential regulation of Ste20 function by the Cln1-Cdc28 and Cln2-Cdc28 cyclin-dependent protein kinases. The Journal of biological chemistry 48 9737966
1998 An essential function of Grr1 for the degradation of Cln2 is to act as a binding core that links Cln2 to Skp1. Journal of cell science 43 9819356
2020 POT1-TPP1 telomere length regulation and disease. Computational and structural biotechnology journal 42 32774788
2019 TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity. Molecular and cellular biology 42 31383750
2014 SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1(Tpp1) to modulate shelterin-Stn1 interaction in fission yeast. Proceedings of the National Academy of Sciences of the United States of America 42 24711392
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2002 The CLN3/SWI6/CLN2 pathway and SNF1 act sequentially to regulate meiotic initiation in Saccharomyces cerevisiae. Genes to cells : devoted to molecular & cellular mechanisms 40 12081645
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2020 Changing Times for CLN2 Disease: The Era of Enzyme Replacement Therapy. Therapeutics and clinical risk management 38 32280231
2018 A Rare Variant P507L in TPP1 Interrupts TPP1-TIN2 Interaction, Influences Telomere Length, and Confers Colorectal Cancer Risk in Chinese Population. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 38 29891727
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2003 The role of yeast DNA 3'-phosphatase Tpp1 and rad1/Rad10 endonuclease in processing spontaneous and induced base lesions. The Journal of biological chemistry 37 12783866
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2011 Multiple POT1-TPP1 proteins coat and compact long telomeric single-stranded DNA. Journal of molecular biology 34 21596049
2016 Structural and functional consequences of a disease mutation in the telomere protein TPP1. Proceedings of the National Academy of Sciences of the United States of America 33 27807141
2015 A docking interface in the cyclin Cln2 promotes multi-site phosphorylation of substrates and timely cell-cycle entry. Current biology : CB 33 25619768
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2014 Partial genetic suppression of a loss-of-function mutant of the neuronal ceroid lipofuscinosis-associated protease TPP1 in Dictyostelium discoideum. Disease models & mechanisms 31 25540127
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2016 The transcription factor RFX5 is a transcriptional activator of the TPP1 gene in hepatocellular carcinoma. Oncology reports 30 27840983
2008 Ccr4 alters cell size in yeast by modulating the timing of CLN1 and CLN2 expression. Genetics 30 18493058
2022 TPP1 promoter mutations cooperate with TERT promoter mutations to lengthen telomeres in melanoma. Science (New York, N.Y.) 29 36356143
2016 Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis. Experimental eye research 29 27637672
2015 The Insertion in Fingers Domain in Human Telomerase Can Mediate Enzyme Processivity and Telomerase Recruitment to Telomeres in a TPP1-Dependent Manner. Molecular and cellular biology 29 26503784
2020 Extracellular Vesicles as Drug Carriers for Enzyme Replacement Therapy to Treat CLN2 Batten Disease: Optimization of Drug Administration Routes. Cells 28 32443895
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2007 CLN2/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype. Molecular genetics and metabolism 28 17959406
2004 Mutation of the glycosylated asparagine residue 286 in human CLN2 protein results in loss of enzymatic activity. Glycobiology 28 14736728
2019 Neurofilament light is a treatment-responsive biomarker in CLN2 disease. Annals of clinical and translational neurology 27 31814335
2015 Protracted late infantile ceroid lipofuscinosis due to TPP1 mutations: Clinical, molecular and biochemical characterization in three sibs. Journal of the neurological sciences 27 26143525
2014 The shelterin component TPP1 is a binding partner and substrate for the deubiquitinating enzyme USP7. The Journal of biological chemistry 26 25172512
2019 POT1-TPP1 differentially regulates telomerase via POT1 His266 and as a function of single-stranded telomere DNA length. Proceedings of the National Academy of Sciences of the United States of America 25 31685617
2013 Akt regulates TPP1 homodimerization and telomere protection. Aging cell 25 23862686
2010 Saccharomyces cerevisiae Ssd1p promotes CLN2 expression by binding to the 5'-untranslated region of CLN2 mRNA. Genes to cells : devoted to molecular & cellular mechanisms 25 20977549
2001 Distribution and development of CLN2 protein, the late-infantile neuronal ceroid lipofuscinosis gene product. Acta neuropathologica 25 11547947
1996 Mitochondrial abnormalities in CLN2 and CLN3 forms of Batten disease. Molecular and chemical neuropathology 25 8971698
2013 Telomere-binding protein TPP1 modulates telomere homeostasis and confers radioresistance to human colorectal cancer cells. PloS one 24 24260532
2000 Neural and extraneural expression of the neuronal ceroid lipofuscinoses genes CLN1, CLN2, and CLN3: functional implications for CLN3. Molecular genetics and metabolism 24 11001812
1997 Overexpression of the G1-cyclin gene CLN2 represses the mating pathway in Saccharomyces cerevisiae at the level of the MEKK Ste11. The Journal of biological chemistry 23 9148934
2020 Symmetric Age Association of Retinal Degeneration in Patients with CLN2-Associated Batten Disease. Ophthalmology. Retina 22 32146219
2016 POT1-TPP1 Binding and Unfolding of Telomere DNA Discriminates against Structural Polymorphism. Journal of molecular biology 22 27173378
2019 Two Separation-of-Function Isoforms of Human TPP1 Dictate Telomerase Regulation in Somatic and Germ Cells. Cell reports 21 31216472
2015 Multifocal retinopathy in Dachshunds with CLN2 neuronal ceroid lipofuscinosis. Experimental eye research 21 25697710
2010 Altered mRNA expression of telomere binding proteins (TPP1, POT1, RAP1, TRF1 and TRF2) in ulcerative colitis and Crohn's disease. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 21 20061197

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