Affinage

TELO2

Telomere length regulation protein TEL2 homolog · UniProt Q9Y4R8

Length
837 aa
Mass
91.7 kDa
Annotated
2026-06-10
20 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TELO2 (HCLK2/Tel2) is a HEAT-repeat scaffolding protein that governs the maturation and signaling competence of phosphatidylinositol-3-kinase-related kinases (PIKKs), thereby coupling chaperone-assisted kinase folding to DNA-damage checkpoint and mTOR growth signaling (PMID:17384638, PMID:34233195). It assembles with TTI1 and TTI2 into the elongated helical TTT co-chaperone complex, in which TTI1 acts as a central platform binding TELO2 and TTI2, and the TELO2 C-terminal domain is required for TTI1 binding and for recruitment of the PIKK ATM (PMID:34838521). The TTT complex engages the kinase domain of TOR without blocking its activity and delivers PIKKs to the R2TP–HSP90 chaperone system, modulating RUVBL1–RUVBL2 ATPase activity and the PIH1D1/RPAP3 components of R2TP (PMID:34233195). In ATR/CHK1 checkpoint signaling, TELO2 associates with ATR–ATRIP, claspin, CHK1, and the ATR activator TopBP1, promotes efficient ATR–TopBP1 association and full ATR kinase activation, and prevents unscheduled proteasomal degradation of CHK1 that is triggered by ATR-mediated CHK1-Ser345 phosphorylation (PMID:17384638, PMID:19097996); this checkpoint function depends on PHD3-mediated prolyl hydroxylation of TELO2, which licenses its interaction with ATR (PMID:22797300). In the mTOR pathway, TELO2 stabilizes mTORC1–substrate interactions in a manner promoted by MNK and opposed by the inhibitor DEPTOR (PMID:28178522), and its abundance is controlled by RICTOR-induced degradation upon serum deprivation, linking TELO2 to tumor cell growth and metastasis (PMID:33416177). Compound heterozygous TELO2 variants reduce steady-state levels of TELO2 and other TTT components, defining a human disease associated with TTT complex destabilization (PMID:27132593).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 High

    Established that TELO2/HCLK2 is a positive regulator of the S-phase DNA-damage checkpoint that physically links ATR signaling components and protects CHK1 from degradation, defining its first mechanistic role.

    Evidence Co-IP, siRNA depletion, epistasis with ATR depletion and CHK1-S345A mutation, and DNA damage/radio-resistant DNA synthesis assays in human cells

    PMID:17384638

    Open questions at the time
    • Did not resolve whether TELO2 acts directly on CHK1 or via stabilizing the upstream kinase
    • Mechanism of TELO2 recruitment to replication stress sites unknown
  2. 2008 High

    Defined how TELO2 contributes to ATR activation, showing it acts together with but at a distinct step from TopBP1 to drive full ATR kinase activity.

    Evidence Co-IP, in vitro ATR kinase assay, siRNA depletion, and checkpoint assays

    PMID:19097996

    Open questions at the time
    • Precise biochemical step regulated by TELO2 distinct from TopBP1 not defined
    • Single-lab in vitro system
  3. 2009 Medium

    Mapped the TELO2 interactome to multiple PIKKs and Fanconi anemia factors, broadening its role from ATR-specific to a central PIKK-associated checkpoint hub.

    Evidence Proteomic/MS pulldown of HCLK2 complexes with functional depletion experiments

    PMID:19282663

    Open questions at the time
    • Direct versus indirect nature of individual interactions not all resolved
    • Functional contribution of DNA-PKcs association not characterized
  4. 2012 High

    Identified a post-translational switch controlling TELO2 checkpoint function: PHD3-mediated prolyl hydroxylation is required for TELO2–ATR interaction and downstream ATR/CHK1/p53 signaling.

    Evidence Hydroxylation assay, Co-IP, PHD3 inhibitor (DMOG)/hypoxia, and PHD3-knockout mouse with apoptosis assays

    PMID:22797300

    Open questions at the time
    • Specific hydroxylated proline residue and its structural consequence not detailed
    • How hypoxia signaling integrates with checkpoint timing unclear
  5. 2016 Medium

    Connected TELO2 to human disease by showing that compound heterozygous variants destabilize TELO2 and the entire TTT complex.

    Evidence Western blotting of patient fibroblasts, exome sequencing, and cellular PIKK functional assays

    PMID:27132593

    Open questions at the time
    • Reported normal PIKK function despite TTT instability leaves genotype–phenotype mechanism unresolved
    • Single patient cohort/lab
  6. 2017 Medium

    Extended TELO2 function to mTORC1 regulation, showing it serves as the node through which MNK (positively) and DEPTOR (negatively) tune mTORC1–substrate engagement.

    Evidence Reciprocal Co-IP, MNK inhibitor/overexpression, rapamycin treatment, and substrate-binding assays

    PMID:28178522

    Open questions at the time
    • Whether TELO2 contacts substrates directly or stabilizes mTORC1 conformation not resolved
    • Single lab
  7. 2017 Medium

    Linked a chaperone-phosphorylation event to TELO2 complex stability, showing Cdc7-Dbf4 phosphorylation of HSP90-Ser164 is required for HSP90-HCLK2-MRN complex stability and ATM/ATR signaling.

    Evidence Phosphoproteomics, in vitro and in vivo kinase assays, Co-IP, siRNA depletion, and DNA repair assays

    PMID:29209046

    Open questions at the time
    • Direct effect of HSP90-S164 phosphorylation on TELO2 folding activity not isolated
    • Single lab
  8. 2020 Medium

    Revealed regulation of TELO2 abundance, showing RICTOR drives serum-deprivation-dependent TELO2 degradation and that TELO2 promotes tumor growth and metastasis through RICTOR.

    Evidence Co-IP, siRNA knockdown, serum deprivation, and cell viability/invasion/cell cycle assays

    PMID:33416177

    Open questions at the time
    • mTOR-independent degradation mechanism (ligase/route) not defined
    • Single lab
  9. 2021 High

    Provided the structural basis for TTT function, showing how the TTT complex engages the TOR kinase domain and delivers PIKKs to R2TP while modulating its ATPase machinery.

    Evidence Cryo-EM structure of human R2TP-TTT plus biochemical ATPase and binding assays

    PMID:34233195

    Open questions at the time
    • Dynamics of the hand-off from TTT to R2TP-HSP90 not captured
    • Generality across all PIKKs beyond TOR not structurally shown
  10. 2021 High

    Resolved the internal architecture of the TTT complex, defining TTI1 as the scaffold and the TELO2 C-terminal domain as essential for TTI1 binding and ATM recruitment and for cell survival after irradiation.

    Evidence Cryo-EM structure at 4.2 Å with domain-deletion mapping and post-IR cell survival assays

    PMID:34838521

    Open questions at the time
    • How the same architecture accommodates different PIKK clients not fully addressed
    • Single lab
  11. 2022 Medium

    Identified TELO2 as a direct small-molecule target, with ivermectin binding the TELO2 C-terminal α-helix to suppress PIKK and AKT/S6K signaling and Wnt/β-catenin activity.

    Evidence Affinity purification with immobilized IVM, resistance-conferring mutagenesis, siRNA knockdown, phosphorylation and β-catenin reporter assays

    PMID:35530256

    Open questions at the time
    • Structural detail of the IVM-binding pocket not solved
    • Mechanistic link between TELO2 and β-catenin beyond mTOR not fully defined
  12. 2026 Medium

    Showed that TELO2 recruitment can be regulated by an upstream adaptor, with PIWIL1 promoting R2TP–TELO2 association to drive mTOR-RAPTOR assembly and TOP mRNA translation independently of piRNAs.

    Evidence Co-IP, PIWIL1-knockout multi-omic profiling, and mTORC1 activity assays in gastric cancer cells

    PMID:42020726

    Open questions at the time
    • Direct versus bridged nature of PIWIL1–TELO2 contact not resolved
    • Generality beyond gastric cancer context unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the TTT complex selectively recognizes, hands off, and times maturation of distinct PIKK clients across DNA-damage and growth-signaling contexts remains incompletely defined.
  • No structural model of the complete TTT-to-R2TP-HSP90 client transfer cycle
  • Determinants of PIKK client selectivity by TELO2 not established
  • Reconciliation of TTT destabilization with normal PIKK function in patients unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0044183 protein folding chaperone 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-73894 DNA Repair 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ATRATRIPDEPTORPIWIL1RICTORTOPBP1TTI1TTI2
Complex memberships
ATR-ATRIP-TopBP1 complexHSP90-HCLK2-MRN complexR2TP-TTT complexTTT complex (TELO2-TTI1-TTI2)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 HCLK2 (TELO2) associates with S-phase checkpoint components ATR, ATRIP, claspin, and Chk1. HCLK2 prevents unscheduled proteasomal degradation of Chk1: ATR phosphorylation of Chk1 at Ser345 both activates Chk1 and targets it for degradation, and HCLK2 depletion accelerates this degradation. Depleting ATR or mutating Chk1-S345 restored Chk1 levels in HCLK2-depleted cells. HCLK2 is also required for claspin phosphorylation, Cdc25A degradation, FANCD2 monoubiquitination, and recruitment of FANCD2 and Rad51 to replication stress sites. Co-immunoprecipitation, siRNA depletion, epistasis by ATR depletion and Chk1-S345A mutation, DNA damage assays, radio-resistant DNA synthesis assay Nature cell biology High 17384638
2008 HCLK2 forms a complex with ATR-ATRIP and the ATR activator TopBP1, facilitates efficient ATR-TopBP1 association, and is required for full-scale ATR kinase activation. HCLK2-induced ATR kinase activity toward substrates requires TopBP1 and vice versa. HCLK2 stimulates ATR autophosphorylation and activity toward substrates in vitro. HCLK2 depletion impairs phosphorylation of multiple ATR targets (Chk1, Nbs1, Smc1), abrogates the G2 checkpoint, and functions in the same pathway as TopBP1 but regulates a different step in ATR activation. Co-immunoprecipitation, in vitro ATR kinase assay, siRNA depletion, checkpoint assays The Journal of biological chemistry High 19097996
2009 Proteomic analysis of HCLK2 complexes identified ATR, ATRIP, DNA-PKcs, and the Fanconi Anemia heterodimer FANCM-FAAP24 as HCLK2-interacting factors. HCLK2/Tel2 binds directly to ATR and other PIKKs and plays a central role in checkpoint signalling. The DNA translocase activity of FANCM is essential for efficient ATR signalling activation downstream of HCLK2. Proteomic/mass spectrometry pulldown of HCLK2 complexes, functional depletion experiments Cell cycle (Georgetown, Tex.) Medium 19282663
2012 HCLK2 is hydroxylated by prolyl hydroxylase domain protein 3 (PHD3). This hydroxylation is necessary for HCLK2's interaction with ATR and for subsequent activation of the ATR/CHK1/p53 pathway. Inhibiting PHD3 (with DMOG or hypoxia) prevents ATR/CHK1/p53 pathway activation and decreases DNA-damage-induced apoptosis. PHD3-knockout mice are resistant to ionizing radiation and have decreased thymic apoptosis. Co-immunoprecipitation, hydroxylation assay, PHD3 inhibitor (DMOG), hypoxia treatment, PHD3-knockout mouse model, apoptosis assays The Journal of clinical investigation High 22797300
2016 TELO2 forms the TTT complex together with TTI1 and TTI2, acting as a co-chaperone for maturation of PIKKs. Compound heterozygous TELO2 variants reduce steady-state levels of TELO2 and other TTT complex components. Despite TTT instability, PIKK functions were reported as normal in patient fibroblast cellular assays. Western blotting of patient fibroblasts, exome sequencing, cellular PIKK functional assays American journal of human genetics Medium 27132593
2017 MNK (MAPK-interacting kinase) sustains mTORC1 activity by promoting mTORC1 association with TELO2, which facilitates mTORC1:substrate binding. DEPTOR (endogenous mTOR inhibitor) opposes mTORC1:substrate association by preventing TELO2:mTORC1 binding. Thus, MNK and DEPTOR exert counterbalancing forces on mTORC1 activity through TELO2. Co-immunoprecipitation, MNK inhibitor/overexpression, rapamycin treatment, substrate binding assays Cell reports Medium 28178522
2017 Cdc7-Dbf4 kinase phosphorylates HSP90 at Ser164, and this phosphorylation is required for stability of the HSP90-HCLK2-MRN complex and for ATM/ATR signaling and homologous recombination DNA repair. HSP90-S164 phosphorylation was identified as a Cdc7-Dbf4 target both in vitro and in vivo by phosphoproteomics. Phosphoproteomics, in vitro kinase assay, in vivo phosphorylation, Co-immunoprecipitation, siRNA depletion, DNA repair assays Scientific reports Medium 29209046
2020 TELO2 binds RICTOR (the rapamycin-insensitive companion of mTOR, a component of mTORC2) by immunoprecipitation. RICTOR induces degradation of TELO2 upon serum deprivation in an mTOR-independent manner. TELO2 promotes tumor cell growth, cell cycle progression, and metastasis via RICTOR in a serum-dependent manner. Co-immunoprecipitation, siRNA knockdown, cell viability/invasion/cell cycle assays, serum deprivation experiments Oncology reports Medium 33416177
2021 Cryo-EM structure of the human R2TP-TTT complex was determined. The HEAT-repeat TTT complex (TELO2-TTI1-TTI2) binds the kinase domain of TOR without blocking its activity, and delivers TOR to the R2TP chaperone. TTT inhibits RUVBL1-RUVBL2 ATPase activity and modulates the conformation and interactions of PIH1D1 and RPAP3 components of R2TP. Cryo-EM structure determination, biochemical ATPase assays, binding/interaction assays Cell reports High 34233195
2021 Cryo-EM structure of the human TTT complex (TELO2-TTI1-TTI2) was determined at 4.2 Å resolution. All three proteins form elongated helical repeat structures. TTI1 provides a platform: TELO2 binds TTI1's central region and TTI2 binds its C-terminal end. The TELO2 C-terminal domain (CTD) is required for interaction with TTI1 and for recruitment of ATM. The N- and C-terminal segments of TTI1 recognize the FAT domain and N-terminal HEAT repeats of ATM respectively. TELO2 CTD and TTI1 terminal segments are required for cell survival after ionizing radiation. Cryo-EM structure determination, domain interaction mapping, cell survival assays after ionizing radiation Journal of molecular biology High 34838521
2022 Ivermectin (IVM) B1a directly binds to TELO2 via affinity purification using immobilized IVM. IVM binding is through the TELO2 C-terminal α-helix; mutations in this helix conferred IVM resistance. TELO2 knockdown reduces cytoplasmic β-catenin and transcriptional activation of β-catenin/TCF. IVM binding to TELO2 reduces PIKK and AKT/S6K phosphorylation levels, linking TELO2 to Wnt/β-catenin signaling through mTOR. Affinity purification with immobilized IVM, mutagenesis conferring drug resistance, siRNA knockdown, phosphorylation assays, β-catenin reporter assays iScience Medium 35530256
2026 PIWIL1 interacts with the R2TP chaperone complex and promotes its association with TELO2, thereby facilitating mTOR-RAPTOR assembly and mTORC1 activation. This promotes translation of 5'-terminal oligopyrimidine (TOP) mRNAs in a piRNA-independent manner in gastric cancer cells. Co-immunoprecipitation, PIWIL1 knockout transcriptomic/translatomic/proteomic profiling, mTORC1 activity assays Oncogene Medium 42020726

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability. Nature cell biology 100 17384638
2020 TELO2 induced progression of colorectal cancer by binding with RICTOR through mTORC2. Oncology reports 83 33416177
2012 PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response. The Journal of clinical investigation 64 22797300
2017 MNK Controls mTORC1:Substrate Association through Regulation of TELO2 Binding with mTORC1. Cell reports 57 28178522
2008 HCLK2 is required for activity of the DNA damage response kinase ATR. The Journal of biological chemistry 38 19097996
2016 A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex. American journal of human genetics 33 27132593
2021 Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone. Cell reports 29 34233195
2017 Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ATM signaling that overcomes replication stress in cancer. Scientific reports 22 29209046
2017 Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome. Molecular genetics & genomic medicine 16 28944240
2017 MNK inversely regulates TELO2 vs. DEPTOR to control mTORC1 signaling. Molecular & cellular oncology 14 28616583
2009 FANCM-FAAP24 and HCLK2: roles in ATR signalling and the Fanconi anemia pathway. Cell cycle (Georgetown, Tex.) 13 19282663
2021 Structure of the Human TELO2-TTI1-TTI2 Complex. Journal of molecular biology 11 34838521
2022 Ivermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases. iScience 9 35530256
2020 Cataract in You-Hoover-Fong syndrome: TELO2 deficiency. Ophthalmic genetics 9 32940098
2023 TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature. American journal of medical genetics. Part A 8 36797513
2016 Overexpression of TELO2 decreases survival in human high-grade gliomas. Oncotarget 8 27329594
2020 Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant. European journal of medical genetics 7 33307281
2023 Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review. Open life sciences 3 37215500
2026 PIWIL1 activates the R2TP-TELO2-mTORC1 axis independently of piRNA to promote TOP mRNA translation in gastric cancer. Oncogene 0 42020726
2025 [Analysis of a child with You-Hoover-Fong syndrome due to compound heterozygous variants of the TELO2 gene and a literature review]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 41645377

Missed literature

Know a paper Affinage missed for TELO2? Flag it for the maintainers and the community.

No submissions yet.