Affinage

TINF2

TERF1-interacting nuclear factor 2 · UniProt Q9BSI4

Length
451 aa
Mass
50.0 kDa
Annotated
2026-06-10
81 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TINF2 (TIN2) is the central organizing subunit of the shelterin complex that protects and length-regulates telomeres, functioning as a protein-protein interaction hub built on a TRFH-like domain that engages TPP1 and TRF2 cooperatively (PMID:29160297, PMID:15316005). It was first identified as a TRF1-binding negative regulator of telomere length whose dominant-negative truncation causes telomerase-dependent telomere elongation (PMID:10581025). TIN2 simultaneously binds TRF1 and TRF2 to link the two double-stranded telomere subcomplexes, and stabilizes their telomeric occupancy (PMID:15316005, PMID:15292264); TPP1 binding expands TIN2's capacity to accommodate both TRF proteins, driving assembly of the stable TRF1-TIN2-TRF2 core and the full six-protein telosome (PMID:16880378, PMID:31158366). TIN2 is the sole bridge tethering the TPP1/POT1 heterodimer to shelterin, and this TIN2-anchored TPP1/POT1 is required to coat single-stranded telomeric DNA, exclude RPA, and repress ATR signaling (PMID:25056954, PMID:22099311). Through TIN2-anchored TPP1 it recruits telomerase and stimulates its processivity via the TPP1 TEL patch, a function genetically separable from end protection (PMID:20404094, PMID:31383750, PMID:26230315). As an architectural protein TIN2 enhances TRF1- and TRF2-mediated telomeric DNA compaction, trans-bridging, and T-loop formation (PMID:34883513, PMID:34403696), and it modulates the TRF1 complex by protecting TRF1 from tankyrase-mediated poly(ADP-ribosyl)ation (PMID:15133513). TIN2 abundance and telomeric residence are controlled by Siah2-dependent ubiquitylation (PMID:22064479) and by phosphorylation inputs including ATR-driven TRF2-S410 phosphorylation that strengthens TRF2-TIN2 binding (PMID:36651296). Beyond telomeres, a processed pool of TIN2 localizes to mitochondria where it regulates oxidative phosphorylation and ROS production (PMID:22885005, PMID:39080375). TINF2 acts as a haploinsufficient tumor suppressor limiting telomere length (PMID:33258446), and dyskeratosis-congenita-associated mutations cause telomere shortening by impairing telomerase recruitment through both telomerase-dependent and -independent routes (PMID:21536674, PMID:24449270, PMID:26230315).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Established TIN2 as a TRF1-associated negative regulator of telomere length, defining the entry point for shelterin-based length control.

    Evidence Interaction cloning, in vitro binding, co-IP and co-localization, with dominant-negative truncation causing telomerase-dependent elongation

    PMID:10581025

    Open questions at the time
    • Did not define how TIN2 connects to other telomere proteins
    • No structural basis for TRF1 binding
  2. 2004 High

    Showed TIN2 physically bridges the TRF1 and TRF2 subcomplexes and stabilizes them at telomeres, identifying TIN2 as the shelterin linchpin.

    Evidence Far-Western, co-IP, yeast two-hybrid, MS and siRNA knockdown with telomeric immunofluorescence

    PMID:15292264 PMID:15316005

    Open questions at the time
    • Did not resolve how TPP1/POT1 connect to this bridge
    • No structural model of the interfaces
  3. 2004 High

    Defined TIN2 as a PARP modulator that protects TRF1 from tankyrase-mediated poly(ADP-ribosyl)ation and as the tether linking POT1 to shelterin via PIP1/TPP1.

    Evidence Ternary complex co-IP, in vitro PARsylation assay, MS identification and shRNA knockdown with telomere-length readout

    PMID:15133513 PMID:15231715

    Open questions at the time
    • Did not establish in vivo significance of PARsylation protection for length control
    • Cis-inhibition mechanism of telomerase not directly visualized
  4. 2004 High

    Demonstrated an essential telomerase-independent function of TIN2 in mammalian development via genetic knockout.

    Evidence TIN2 knockout mouse with TERT-knockout epistasis showing non-rescuable embryonic lethality

    PMID:15254230

    Open questions at the time
    • Molecular basis of the telomerase-independent essential role not defined
  5. 2006 High

    Reconstituted the six-protein telosome and showed TPP1 cooperatively stabilizes the TRF1-TIN2-TRF2 bridge, clarifying assembly logic.

    Evidence In vitro reconstitution, co-IP, shRNA knockdown and overexpression

    PMID:16880378

    Open questions at the time
    • Stoichiometry and dynamics of assembly not resolved at this stage
  6. 2008 High

    Pinpointed TIN2's major protective role as stabilizing TPP1/POT1a on the single-stranded overhang to exclude RPA and repress ATR.

    Evidence Conditional TIN2 deletion in mouse cells with shelterin/RPA localization and kinase signaling assays

    PMID:22099311

    Open questions at the time
    • Relative contribution to ATM repression remained minor and incompletely defined
  7. 2010 High

    Established that TIN2-anchored TPP1 recruits telomerase to telomeres, linking the architectural hub to active telomere extension.

    Evidence shRNA depletion with telomerase FISH and ChIP plus TPP1 OB-fold mutagenesis

    PMID:20404094

    Open questions at the time
    • Did not separate recruitment from processivity stimulation at the molecular level
  8. 2011 High

    Defined post-translational control of TIN2 levels and telomeric residence via Siah2-mediated ubiquitylation.

    Evidence Co-IP, in vivo and in vitro ubiquitylation with purified proteins, siRNA depletion and RING-dependent overexpression

    PMID:22064479

    Open questions at the time
    • Physiological signals triggering Siah2-dependent TIN2 turnover not identified
  9. 2011 Medium

    Linked dyskeratosis-congenita TIN2 mutations to defective telomerase recruitment rather than end-protection failure.

    Evidence Ectopic DC-mutant expression with telomere-length, TERC/telomerase co-IP and end-protection assays

    PMID:21536674

    Open questions at the time
    • Single-lab co-IP-based association with TERC
    • Endogenous-allele confirmation came later
  10. 2014 High

    Genetically proved TIN2 is the sole shelterin link to TPP1/POT1 and that a TRF2-tethered TIN2/TPP1/POT1 module suffices for end protection.

    Evidence Separation-of-function TIN2 alleles (TIN2ΔTPP1, TIN2-L247E with Rap1-RCT fusion) by gene targeting and protection assays; DC knock-in epistasis with mTR-/-

    PMID:24449270 PMID:24469404 PMID:25056954

    Open questions at the time
    • Mechanism of the telomerase-independent shortening / fragile telomere phenotype not fully resolved
  11. 2015 High

    Showed at single-telomere resolution that the DC mutation R282H reduces telomerase elongation frequency independent of protection, cementing a dedicated recruitment role.

    Evidence CRISPR knock-in of TIN2-R282H with single-telomere extension and telomerase co-localization assays

    PMID:26230315

    Open questions at the time
    • Did not define the precise contact that couples TIN2 to telomerase
  12. 2017 High

    Provided the structural basis for the shelterin hub by showing TIN2 has a TRFH-like platform engaging TPP1 and TRF2 cooperatively.

    Evidence X-ray crystallography of TIN2 N-terminal domain with TPP1/TRF2 motifs, structure-based mutagenesis and protection assays

    PMID:29160297

    Open questions at the time
    • TRF1 interface not crystallized in this study
    • Full assembled shelterin architecture not solved
  13. 2019 High

    Defined the biochemical mechanism of telomerase processivity stimulation and the single-molecule dynamics of core-complex assembly.

    Evidence In vitro telomerase activity assay with TPP1 TEL-patch mutagenesis; fluorescence cross-correlation spectroscopy of reconstituted complexes

    PMID:31158366 PMID:31383750

    Open questions at the time
    • Single-method (FCCS) for the binding-capacity expansion model
    • In vivo relevance of TPP1-driven expansion not directly tested
  14. 2021 High

    Established TIN2 as an architectural protein that enhances TRF1/TRF2-mediated telomeric DNA compaction, trans-bridging, and T-loop formation, and is regulated by tankyrase and TPP1.

    Evidence Single-molecule fluorescence, AFM and DNA tightrope assays with purified TRF1/TRF2 and TIN2 isoforms

    PMID:34403696 PMID:34883513

    Open questions at the time
    • In vivo contribution of TIN2 architectural activity to telomere structure not directly measured
  15. 2020 High

    Established TINF2 as a haploinsufficient tumor suppressor for telomere length, with single-allele truncations causing elongation while preserving protection.

    Evidence Heterozygous knock-in/deletion by gene targeting with clonal telomere-length and protection analyses

    PMID:33258446

    Open questions at the time
    • Mechanistic link between specific truncations and dosage-sensitive length control not fully resolved
  16. 2012 Medium

    Revealed an extra-telomeric mitochondrial pool of TIN2 regulating oxidative phosphorylation and ROS, controlled by TPP1-binding targeting sequences.

    Evidence Subcellular fractionation, co-localization, targeting-sequence mapping and metabolic/ROS assays after knockdown

    PMID:22885005

    Open questions at the time
    • Single-lab finding
    • Direct biochemical activity of TIN2 within mitochondria not defined
  17. 2024 Medium

    Extended the mitochondrial role by showing TIN2 drives FOXO1 phosphorylation and mitochondrial translocation to suppress respiration and antioxidant defense.

    Evidence Co-IP, fractionation, ChIP for FOXO1 at mtDNA D-loop with knockdown/overexpression in RPE cells under hyperglycemia

    PMID:39080375

    Open questions at the time
    • Single-lab, disease-context-specific
    • Direct TIN2-FOXO1 enzymatic relationship not established
  18. 2025 High

    Structurally characterized a druggable hotspot at the TRF1:TIN2 interface, enabling first-in-class inhibitors that dissociate shelterin.

    Evidence X-ray fragment screening, NMR, fluorescence polarization displacement and shelterin dissociation assays with purified proteins

    PMID:41266376

    Open questions at the time
    • Low-affinity fragment-stage compounds
    • Cellular efficacy not yet demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the architectural compaction, telomerase-recruitment, and mitochondrial functions of TIN2 are coordinately regulated across the cell cycle and in disease remains unresolved.
  • Integrated regulation of phosphorylation (RSK2, ATR/TRF2-S410), ubiquitylation (Siah2), and isoform usage not unified
  • In vivo significance of mitochondrial TIN2 versus telomeric TIN2 not separated genetically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 3 GO:0003677 DNA binding 2 GO:0005198 structural molecule activity 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
FOXO1POT1RAP1SIAH2TNKSTPP1TRF1TRF2
Complex memberships
shelterin/telosome

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TIN2 was identified as a TRF1-interacting protein by interaction cloning; it interacts with TRF1 in vitro and in cells, co-localizes with TRF1 at nuclei and metaphase chromosomes, and an N-terminal truncation mutant of TIN2 causes telomere elongation in a telomerase-dependent manner, establishing TIN2 as a negative regulator of telomere length that mediates TRF1 function. Interaction cloning (yeast two-hybrid), in vitro binding assay, co-immunoprecipitation, co-localization by immunofluorescence, dominant-negative overexpression with telomere-length measurement Nature genetics High 10581025
2004 TIN2 directly binds both TRF1 and TRF2 simultaneously, linking the TRF1 and TRF2 complexes; TIN2 depletion by siRNA reduces TRF2 and hRap1 at telomeres, demonstrating that TIN2 stabilizes TRF2 on telomeres. Mass spectrometry, co-immunoprecipitation, Far-Western assay, yeast two-hybrid, siRNA knockdown with immunofluorescence quantification, gel filtration The Journal of biological chemistry High 15316005
2004 TIN2 forms a ternary complex with TRF1 and tankyrase 1, stabilizes their interaction, and protects TRF1 from poly(ADP-ribosyl)ation by tankyrase 1 in vitro without affecting tankyrase 1 automodification, thereby acting as a PARP modulator in the TRF1 complex to regulate telomere length. Co-immunoprecipitation (ternary complex), in vitro poly(ADP-ribosyl)ation assay, siRNA/shRNA knockdown with telomere-length measurement, PARP inhibitor rescue, dominant-negative overexpression Nature genetics High 15133513
2004 TIN2 mediates functions of TRF2 at telomeres; TIN2 interacts with TRF2 in vitro and in cells, and TIN2 mutants defective in binding TRF1 or TRF2 induce a DNA damage response and destabilize both TRF1 and TRF2 at telomeres. In vitro binding assay, yeast two-hybrid, co-immunoprecipitation in mammalian cells, dominant-negative overexpression with immunofluorescence The Journal of biological chemistry High 15292264
2004 TIN2 interacts with PIP1 (TPP1) and bridges TRF1 to POT1; PIP1 tethers POT1 to the TRF1/TIN2 complex, and shRNA-mediated reduction of PIP1 or POT1 causes telomere elongation, establishing the TRF1-TIN2-PIP1-POT1 pathway for cis-inhibition of telomerase. Mass spectrometry identification, co-immunoprecipitation, shRNA knockdown with telomere-length measurement Genes & development High 15231715
2004 TIN2 is essential for early embryonic development through a telomerase-independent pathway; homozygous TIN2 gene knockout in mice causes early embryonic lethality that is not rescued by inactivation of the telomerase reverse transcriptase gene. Gene targeting (knockout mouse), genetic epistasis with TERT knockout Molecular and cellular biology High 15254230
2003 TIN2 stimulates TRF1-mediated clustering/interactions between telomeric DNA tracts in vitro (5–10-fold enhancement), and a dominant-negative TIN2 mutant that elongates telomeres in vivo disrupts these clusters, suggesting TIN2 promotes a higher-order telomeric structure that restricts telomerase access. In vitro telomeric DNA probe-clustering assay with biotinylated probes and streptavidin-agarose, dominant-negative protein competition EMBO reports Medium 12835755
2006 TIN2 and TPP1 are both required to bridge the TRF1 and TRF2 subcomplexes into the full six-protein shelterin/telosome complex; TPP1 stabilizes the TRF1-TIN2-TRF2 interaction, and TPP1 knockdown reduces TRF1 association with the TRF2 complex. Reconstitution of six-protein complex in vitro, co-immunoprecipitation, shRNA knockdown, overexpression Proceedings of the National Academy of Sciences of the United States of America High 16880378
2008 TIN2 deletion in mouse cells causes loss of TPP1/POT1a from telomeres, accumulation of RPA, and ATR kinase activation, establishing TIN2's major role as stabilizing TPP1/POT1a on single-stranded telomeric DNA to exclude RPA and repress ATR signaling; TIN2 also has a minor contribution to ATM repression by TRF2. Conditional gene deletion (TIN2 knockout mouse cells), immunofluorescence for telomere localization of shelterin proteins and RPA, kinase signaling assays Molecular cell High 22099311
2010 TIN2-anchored TPP1 is required for telomerase recruitment to telomeres in human cells; depletion of TIN2 or TPP1 by shRNA reduces telomerase association with telomeres as measured by FISH and ChIP, and the OB-fold of TPP1 is required for this recruitment. shRNA depletion, telomerase FISH, chromatin immunoprecipitation (ChIP), deletion mutagenesis of TPP1 OB-fold Molecular and cellular biology High 20404094
2011 TIN2 stability is regulated by the E3 ubiquitin ligase Siah2: TIN2 binds Siah2, is ubiquitylated in vivo, and Siah2 directly ubiquitylates TIN2 in vitro using purified proteins; Siah2 depletion stabilizes TIN2 protein levels and Siah2 overexpression removes TIN2 from telomeres in a RING-domain-dependent manner. Co-immunoprecipitation, in vivo ubiquitylation assay, in vitro ubiquitylation assay with purified proteins, siRNA depletion, overexpression with immunofluorescence Molecular and cellular biology High 22064479
2011 DC-associated TIN2 missense mutations (e.g., R282H) lead to accelerated telomere shortening in human cells without altering total telomerase activity, TIN2 localization, or telomere end-protection status; instead, DC mutations reduce TIN2's ability to associate with TERC and telomerase activity, impairing TPP1-dependent telomerase recruitment. Ectopic expression of DC mutant TIN2 in human cells, telomere-length measurement, co-immunoprecipitation with TERC/telomerase, telomere end-protection assays The Journal of biological chemistry Medium 21536674
2012 TIN2 is posttranslationally processed and localizes to mitochondria in addition to telomeres; TPP1 interacts with the TIN2 N-terminus (which contains overlapping mitochondrial and telomeric targeting sequences) and controls TIN2 localization; mitochondria-localized TIN2 regulates oxidative phosphorylation and ROS production. Subcellular fractionation, immunofluorescence co-localization, RNAi knockdown with metabolic assays (glycolysis, oxygen consumption, ROS measurement), deletion/truncation mapping of targeting sequences Molecular cell Medium 22885005
2013 TIN2 is phosphorylated at serines 295 and 330 during mitosis in human cells, mediated at least in part by the mitotic kinase RSK2, which phosphorylates TIN2 in vitro. Phosphoproteomic analysis, Phos-tag gel electrophoresis, phosphorylation-specific antibodies, RSK2 overexpression and kinase inhibitor treatment, in vitro kinase assay PloS one Medium 23977114
2014 TIN2 is the sole link between TPP1/POT1 heterodimers and the shelterin complex; a TIN2 allele deficient for TPP1 binding (TIN2ΔTPP1) but retaining TRF1 and TRF2 binding fully phenocopies the POT1a/b knockout phenotype without additional phenotypes, establishing that no other shelterin component contributes to TPP1/POT1 recruitment. Gene targeting to introduce separation-of-function TIN2 allele (TIN2ΔTPP1), telomere protection assays, immunofluorescence, comparison with POT1a/b KO phenotype The Journal of biological chemistry High 25056954
2014 TIN2 requires interaction with TRF1 for optimal loading onto telomeres; a TRF1-binding-deficient TIN2 allele (TIN2-L247E) fused to TRF2-interacting Rap1-RCT bypasses the TRF1-loading requirement and is fully functional for chromosome-end protection by TRF2 and TPP1/POT1, demonstrating that a TRF2-tethered TIN2/TPP1/POT1 complex is sufficient for telomere protection. Gene targeting with separation-of-function alleles, Rap1-RCT fusion bypass approach, telomere protection assays, immunofluorescence Molecular and cellular biology High 24469404
2014 A TIN2 DC mutation (K280E equivalent in mouse) causes telomere shortening through both telomerase-dependent and telomerase-independent mechanisms; TIN2(+/DC) mTR−/− mice showed accelerated telomere shortening compared to TIN2(+/+) mTR−/− controls, and the DC allele induced a fragile telomere phenotype suggestive of replication problems. Gene targeting to knock in DC allele in mice, intercrossing with mTR−/− mice (genetic epistasis), telomere FISH, ATR signaling assays, fragile telomere scoring Genes & development High 24449270
2015 The TIN2-R282H DC mutation reduces the frequency of telomerase elongation at individual telomeres without disrupting shelterin occupancy, telomere damage signaling, or end protection, establishing a direct role for TIN2 in telomerase recruitment separable from its telomere-protection function. CRISPR/knock-in of TIN2-R282H in human cells, single-telomere extension assay (STELA-related), telomerase-telomere co-localization, DNA damage marker analysis PLoS genetics High 26230315
2017 Crystal structure of the N-terminal domain of TIN2 in complex with TIN2-binding motifs from TPP1 and TRF2 reveals that TIN2 contains a TRFH-like domain that functions as a protein-protein interaction platform and that TIN2 interacts cooperatively with TPP1 and TRF2; structure-based mutagenesis confirmed the functional importance of these interfaces for stable shelterin assembly and telomere end protection. X-ray crystallography, structure-based mutagenesis, co-immunoprecipitation validation of mutant interactions, telomere protection assays Cell research High 29160297
2018 TIN2L (long isoform), but not TIN2S, is phosphorylated, and this phosphorylation promotes enhanced interaction with TRF2; the DC cluster region in TIN2L further enhances TRF2 interaction. TRF2-F120 mediates TIN2L-specific interaction. TRF1 interacts more with TIN2S than TIN2L. Cells overexpressing TIN2L or phosphomimetic TIN2L permit telomere elongation, while TIN2S or phosphodead TIN2L do not. Co-immunoprecipitation of isoform-specific interactions, phosphorylation-specific antibodies, CRISPR/Cas9 elimination of TIN2L, overexpression of phosphomimetic/phosphodead mutants, telomere-length measurement Molecular and cellular biology Medium 29581185
2018 Loss of the RNA-binding protein HuR during replicative senescence increases TIN2 protein levels by destabilizing TIN2 mRNA and reducing its translation; elevated TIN2 enhances mitochondrial localization of TIN2, increases ROS production, and contributes to cellular senescence induction and maintenance. RIP (RNA immunoprecipitation) of HuR-TIN2 mRNA interaction, HuR depletion with ROS and mitochondrial localization readouts, SA-β-gal senescence assays Nucleic acids research Medium 29584879
2019 TIN2 (all three isoforms including newly identified TIN2M) stimulates telomerase processivity in vitro; this stimulation requires the TPP1 TEL patch, establishing that TIN2 functions together with TPP1/POT1 as a functional shelterin subcomplex to stimulate telomerase. Direct telomerase activity assay in vitro, identification of TIN2M isoform by cDNA cloning, immunofluorescence localization, TPP1 TEL-patch mutagenesis Molecular and cellular biology High 31383750
2019 At the single-molecule level, TRF1 can substitute for TRF2 on TIN2 when TPP1 is absent; upon TPP1 binding, TIN2 binding capacity expands to simultaneously accommodate both TRF1 and TRF2, providing a mechanism for TPP1-driven stable TRF1-TIN2-TRF2 core complex formation. Fluorescence cross-correlation spectroscopy (FCCS) of single molecules in solution, reconstitution of TRF1-TIN2-TRF2 and TPP1-containing complexes Journal of molecular biology Medium 31158366
2020 TINF2 is haploinsufficient for telomere length control; heterozygous deletion or truncating knock-in mutations of TINF2 result in excessive telomere elongation in clonal lines while telomere protection and genome stability are maintained, establishing TINF2 as a haploinsufficient tumor suppressor that limits telomere length. Heterozygous knock-in of truncating mutations by gene targeting, clonal analysis of telomere length, TINF2 heterozygous deletion, telomere protection assays eLife High 33258446
2021 TIN2S and TIN2L isoforms facilitate TRF2-mediated telomeric DNA compaction (cis-interactions) and dsDNA-dsDNA, dsDNA-ssDNA, and dsDNA-ssRNA bridging (trans-interactions); TIN2 also facilitates TRF2-mediated T-loop formation, functioning as an architectural protein for higher-order telomeric nucleic acid structures. Single-molecule fluorescence imaging of DNA compaction, atomic force microscopy (AFM), DNA tightrope assay, reconstitution with purified TRF2 and TIN2 isoforms Nucleic acids research High 34883513
2021 TIN2 short and long isoforms facilitate TRF1-mediated telomeric DNA compaction (cis-interactions) and DNA-DNA bridging (trans-interactions) in a telomeric sequence- and length-dependent manner; Tankyrase 1 + NAD+ reduces TRF1-TIN2-mediated bridging, while TIN2 protects against Tankyrase-induced disassembly; TPP1 inhibits TRF1-TIN2L-mediated DNA-DNA bridging. Atomic force microscopy (AFM), total internal reflection fluorescence microscopy (TIRFM), DNA tightrope assay, reconstitution with purified proteins The Journal of biological chemistry High 34403696
2022 Introducing TIN2-DC mutations (T284R) in human embryonic stem cells (hESCs) causes short-telomere phenotype without triggering telomere DNA damage responses; frameshift mutation at exon 2 of TINF2 disrupts the mutant allele and restores telomere length, validating a gene-editing therapeutic strategy. CRISPR knock-in of DC mutations in hESCs and HSPCs, telomere-length measurement, DNA damage response assays, gene editing at exon 2 Blood Medium 35421215
2022 TIN2 deficiency (homozygous Tin2S341X) in mouse embryonic stem cells causes ALT-associated phenotypes (excessively long heterogeneous telomeres, increased ALT-PML bodies, unstable chromosome ends), elevated Zscan4, and increased DAXX/ATRX and H3K9me3 at telomeres; mutant mESCs are impaired in differentiation, and differentiated cells show elevated telomeric DNA damage. Gene targeting in mESCs (homozygous truncation allele), ALT marker assays (FISH, CO-FISH, PML body immunofluorescence), ChIP for DAXX/ATRX/H3K9me3, differentiation assays Stem cell reports Medium 35395177
2023 ATR-mediated phosphorylation of TRF2 at S410 stimulates TRF2 interaction with TIN2 both in vitro and at telomeres; PPM1D phosphatase dephosphorylates TRF2-S410 and its inhibition increases TIN2 and TPP1 occupancy at telomeres, while PPM1D overexpression reduces TIN2 and TPP1 at telomeres. Proximity biotinylation proteomics, co-immunoprecipitation, confocal microscopy, in vitro binding assay with phosphorylated TRF2, PPM1D inhibition/overexpression with chromatin immunoprecipitation readouts Nucleic acids research Medium 36651296
2024 Mitochondria-localized TIN2 promotes phosphorylation of FOXO1 and its translocation to mitochondria; mitochondrial FOXO1 binds the D-loop region of mitochondrial DNA to inhibit mitochondrial respiration and is sequestered from nuclear target genes, weakening antioxidant defense and inducing RPE cell apoptosis under hyperglycemia. Co-immunoprecipitation, immunofluorescence, mitochondrial fractionation, ChIP for FOXO1 at mtDNA D-loop, TIN2 knockdown/overexpression with metabolic and apoptosis readouts Cell death and differentiation Medium 39080375
2025 Fragment screening (X-ray crystallography and NMR) identified first-in-class inhibitors of the TRF1:TIN2 protein-protein interaction; compound 40 binds TRF1TRFH at the TIN2 interface (KD 29 µM), displaces a TIN2-TBM peptide probe (IC50 67 µM), and expels TRF1 from purified shelterin complex, structurally characterizing a hotspot at the TRF1:TIN2 interface. X-ray crystallography (XChem fragment screening), ligand-observed NMR, fluorescence polarization displacement assay, shelterin complex dissociation assay with purified proteins Scientific reports High 41266376
2005 During growth arrest of human mammary epithelial cells, TIN2 reorganizes into one to three large nuclear subdomains that do not contain telomeres; expression of truncated TIN2 forms simultaneously prevents these domain formations and relaxes morphogenesis-induced growth arrest, indicating an extra-telomeric role for TIN2 in controlling cell proliferation. Immunofluorescence with telomere FISH (co-localization analysis), truncated TIN2 overexpression with proliferation/morphogenesis assays, DNase/RNase sensitivity Journal of cell science Medium 15741234
2009 A TIN2 isoform (TIN2L) containing an additional 97 amino acids associates strongly with the nuclear matrix and cannot be extracted by stringent salt and detergent conditions, unlike TIN2S; in mammary epithelial cells, each isoform shows a distinct nuclear distribution as a function of cell cycle position and telomere length. Nuclear matrix fractionation with salt/detergent extraction, immunofluorescence, isoform-specific antibodies, cell cycle analysis Cell cycle (Georgetown, Tex.) Medium 19229133
2011 Two TIN2 subcomplexes with distinct functions exist in human cells; a TIN2 mutant unable to bind TRF2 (TIN2-15C) is more potent than one unable to bind TRF1 (TIN2-13) in causing telomere uncapping and growth arrest in p53-competent cells, or cell death in p53-deficient cells. Biochemical isolation of TIN2 subcomplexes from nuclear lysates, TIN2 mutant overexpression, telomere uncapping assays, cell survival assays The Journal of cell biology Medium 18443218

Source papers

Stage 0 corpus · 81 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 TIN2, a new regulator of telomere length in human cells. Nature genetics 418 10581025
2004 POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes & development 354 15231715
2008 TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. American journal of human genetics 321 18252230
2004 TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. The Journal of biological chemistry 260 15316005
2008 TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood 246 18669893
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
2011 Telomere protection by TPP1/POT1 requires tethering to TIN2. Molecular cell 189 22099311
2004 TIN2 mediates functions of TRF2 at human telomeres. The Journal of biological chemistry 159 15292264
2004 TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nature genetics 154 15133513
2015 Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis. Chest 144 25539146
2005 Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis. The American journal of pathology 116 15632001
2012 Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control. Molecular cell 88 22885005
2017 Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. Cell research 74 29160297
2011 Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. Clinical genetics 69 21477109
2014 TRF2-tethered TIN2 can mediate telomere protection by TPP1/POT1. Molecular and cellular biology 68 24469404
2006 Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T-cell leukemia. International journal of cancer 67 16786598
2004 Telomere-associated protein TIN2 is essential for early embryonic development through a telomerase-independent pathway. Molecular and cellular biology 65 15254230
2010 Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer. Journal of cancer research and clinical oncology 61 20127252
2002 Down-regulation of TRF1, TRF2 and TIN2 genes is important to maintain telomeric DNA for gastric cancers. Anticancer research 59 12530079
2015 The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres. PLoS genetics 53 26230315
2020 TINF2 is a haploinsufficient tumor suppressor that limits telomere length. eLife 52 33258446
2011 TIN2 protein dyskeratosis congenita missense mutants are defective in association with telomerase. The Journal of biological chemistry 52 21536674
2018 Neofunctionalization of the secreted Tin2 effector in the fungal pathogen Ustilago maydis. Nature microbiology 46 30510169
2008 Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes. The Journal of cell biology 46 18443218
2019 TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity. Molecular and cellular biology 42 31383750
2018 Loss of RNA-binding protein HuR facilitates cellular senescence through posttranscriptional regulation of TIN2 mRNA. Nucleic acids research 42 29584879
2014 A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice. Genes & development 42 24449270
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
2003 The human telomere-associated protein TIN2 stimulates interactions between telomeric DNA tracts in vitro. EMBO reports 38 12835755
2005 Higher-order nuclear organization in growth arrest of human mammary epithelial cells: a novel role for telomere-associated protein TIN2. Journal of cell science 37 15741234
2020 A Truncating Germline Mutation of TINF2 in Individuals with Thyroid Cancer or Melanoma Results in Longer Telomeres. Thyroid : official journal of the American Thyroid Association 36 31928178
2009 A novel form of the telomere-associated protein TIN2 localizes to the nuclear matrix. Cell cycle (Georgetown, Tex.) 36 19229133
2014 Binding of TPP1 protein to TIN2 protein is required for POT1a,b protein-mediated telomere protection. The Journal of biological chemistry 35 25056954
2011 Telomere length measurement can distinguish pathogenic from non-pathogenic variants in the shelterin component, TIN2. Clinical genetics 34 21199492
2008 Ataxia and pancytopenia caused by a mutation in TINF2. Human genetics 27 18979121
2018 The C-Terminal Extension Unique to the Long Isoform of the Shelterin Component TIN2 Enhances Its Interaction with TRF2 in a Phosphorylation- and Dyskeratosis Congenita Cluster-Dependent Fashion. Molecular and cellular biology 24 29581185
2011 TIN2 stability is regulated by the E3 ligase Siah2. Molecular and cellular biology 24 22064479
2016 TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis. Case reports in pulmonology 23 27088026
2002 A human interstitial telomere associates in vivo with specific TRF2 and TIN2 proteins. European journal of human genetics : EJHG 23 11938440
2024 TIN2-mediated reduction of mitophagy induces RPE senescence under high glucose. Cellular signalling 19 38657846
2017 Retinal findings and a novel TINF2 mutation in Revesz syndrome: Clinical and molecular correlations with pediatric retinal vasculopathies. Ophthalmic genetics 19 28095086
2022 Editing TINF2 as a potential therapeutic approach to restore telomere length in dyskeratosis congenita. Blood 17 35421215
2018 A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita. Medicine 17 29742735
2010 A child with severe form of dyskeratosis congenita and TINF2 mutation of shelterin complex. Pediatric blood & cancer 17 20979174
2021 TIN2 is an architectural protein that facilitates TRF2-mediated trans- and cis-interactions on telomeric DNA. Nucleic acids research 16 34883513
2013 Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post-hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation. Pediatric transplantation 16 24168326
2024 TIN2 modulates FOXO1 mitochondrial shuttling to enhance oxidative stress-induced apoptosis in retinal pigment epithelium under hyperglycemia. Cell death and differentiation 14 39080375
2016 Robust DNA Damage Response and Elevated Reactive Oxygen Species in TINF2-Mutated Dyskeratosis Congenita Cells. PloS one 14 26859482
2012 Mitochondria and telomeres: the promiscuous roles of TIN2. Molecular cell 14 23020852
2003 Mus musculus and Mus spretus homologues of the human telomere-associated protein TIN2. Genomics 14 12676566
2023 Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres. Nucleic acids research 10 36651296
2015 Novel Mutation of the TINF2 Gene in a Patient with Dyskeratosis Congenita. Case reports in dermatology 9 26351433
2022 TIN2 deficiency leads to ALT-associated phenotypes and differentiation defects in embryonic stem cells. Stem cell reports 8 35395177
2019 Human Telomere Repeat Binding Factor TRF1 Replaces TRF2 Bound to Shelterin Core Hub TIN2 when TPP1 Is Absent. Journal of molecular biology 8 31158366
2023 TINF2 is a major susceptibility gene in Danish patients with multiple primary melanoma. HGG advances 7 37646013
2021 Structure, dynamics, and regulation of TRF1-TIN2-mediated trans- and cis-interactions on telomeric DNA. The Journal of biological chemistry 7 34403696
2021 Tissue-specific telomere shortening and degenerative changes in a patient with TINF2 mutation and dyskeratosis congenita. Human pathology (New York) 7 34522616
2018 The structurally similar TRFH domain of TRF1 and TRF2 dimers shows distinct behaviour towards TIN2. Archives of biochemistry and biophysics 6 29428209
2016 Molecular basis and quantitative assessment of TRF1 and TRF2 protein interactions with TIN2 and Apollo peptides. European biophysics journal : EBJ 6 27450562
2013 Irreversible leukoencephalopathy after reduced-intensity stem cell transplantation in a dyskeratosis congenita patient with TINF2 mutation. Journal of pediatric hematology/oncology 6 23242325
2011 Transcriptional activation of TINF2, a gene encoding the telomere-associated protein TIN2, by Sp1 and NF-κB factors. PloS one 6 21731707
2018 Effects of TIN2 on telomeres and chromosomes in the human gastric epithelial cell line GES-1. Oncology letters 5 29552152
2015 Three of a Kind: Genetically Similar Tsukamurella Phages TIN2, TIN3, and TIN4. Applied and environmental microbiology 5 26187971
2017 A novel spliced variant of the TIN2 shelterin is present in chronic lymphocytic leukemia. Leukemia research 4 28575699
2001 The human TINF2 gene organisation and chromosomal localization. Biochimie 4 11368852
2013 Cell cycle regulated phosphorylation of the telomere-associated protein TIN2. PloS one 3 23977114
2023 A de novo TINF2, R282C Mutation in a Case of Dyskeratosis Congenital Founded by Next-Generation Sequencing. Iranian biomedical journal 2 37070599
2023 Assembly path dependence of telomeric DNA compaction by TRF1, TIN2, and SA1. Biophysical journal 2 37081787
2022 Autoimmune Neutropenia and Immune-Dysregulation in a Patient Carrying a TINF2 Variant. International journal of molecular sciences 2 36498862
2024 Novel truncating germline variant reinforces TINF2 as a susceptibility gene for familial non-medullary thyroid cancer. Journal of medical genetics 1 39103207
2022 Truncating TINF2 p.Tyr312Ter variant and inherited breast cancer susceptibility. Familial cancer 1 35590014
2022 Novel TINF2 gene mutation in dyskeratosis congenita with extremely short telomeres: A case report. World journal of clinical cases 1 36483815
2017 Gene dosage reductions of Trf1 and/or Tin2 induce telomere DNA damage and lymphoma formation in aging mice. Leukemia 1 29130457
2025 C-Terminal Extended Domain-Independent Telomere Maintenance: Modeling the Function of TIN2 Isoforms in Mus musculus. International journal of molecular sciences 0 40141057
2025 Jasmonic acid signalling is targeted by a smut fungal Tin2-fold effector. Journal of experimental botany 0 40891345
2025 Discovery of first-in-class inhibitors of the TRF1:TIN2 protein:protein interaction by fragment screening. Scientific reports 0 41266376
2024 IGF2BPs-regulated TIN2 confers the malignant biological behaviors of gastric cancer cells. Tissue & cell 0 39765136
2022 A Rare Heterozygous TINF2 Deletional Frameshift Mutation in a Chinese Pedigree With a Spectrum of TBDs Phenotypes. Frontiers in genetics 0 35873475
2022 de Novo TINF2 C.845G>A: Pathogenic Variant in Patient with Dyskeratosis Congenita. Balkan journal of medical genetics : BJMG 0 36249522
2013 [mRNA expression of telomere protection protein TIN2 and POT1 in bone marrow of patients with myelodysplastic syndrome]. Zhongguo shi yan xue ye xue za zhi 0 23484702

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