Affinage

POT1

Protection of telomeres protein 1 · UniProt Q9NUX5

Length
634 aa
Mass
71.4 kDa
Annotated
2026-04-28
100 papers in source corpus 50 papers cited in narrative 50 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POT1 is a telomere-dedicated single-stranded DNA-binding protein that protects chromosome ends from being recognized as DNA damage, regulates telomerase access, and coordinates C-strand fill-in synthesis. Its two N-terminal OB folds bind the telomeric sequence 5'-TTAGGGTTAG-3' with high specificity, discriminating DNA from RNA through a hydrophobic pocket surrounding a critical thymidine residue, while a third OB fold and Holliday junction resolvase-like domain in the C-terminus mediate interaction with TPP1, which is essential for telomeric localization via the TIN2–TRF1/TRF2 shelterin bridge and for suppressing ATR-dependent DNA damage signaling by excluding RPA from the single-stranded overhang (PMID:11349150, PMID:15558049, PMID:20080730, PMID:17687332, PMID:28393830, PMID:22099311). POT1 exerts dual control over telomerase: it inhibits extension when occupying the DNA 3'-terminus but enhances telomerase processivity when positioned one repeat internally, and the POT1–TPP1 heterodimer unfolds G-quadruplex structures by conformational selection, resolves replication barriers, and stimulates WRN/BLM helicases at telomeric substrates (PMID:15792951, PMID:32232414, PMID:20094033, PMID:16030011). POT1 also recruits the CST–Polα/primase complex through phosphorylation-dependent interactions at its hinge region, holding this machinery in an autoinhibited state until dephosphorylation triggers C-strand fill-in synthesis, and its 'POT-hole' surface recognizes the phosphorylated 5' junction to define precise chromosome end structure (PMID:38838667, PMID:37590346, PMID:15973431). Germline POT1 mutations cause Coats plus syndrome through defective C-strand maintenance and telomere truncation, while somatic cancer-associated mutations in OB folds or the TPP1-interaction domain drive telomere elongation and genomic instability (PMID:27013236, PMID:33934394).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    The fundamental question of what protects single-stranded telomeric DNA was answered by the identification of POT1 as the terminal ssDNA-binding factor whose loss causes immediate telomere loss and chromosome circularization.

    Evidence Genetic deletion of pot1+ in S. pombe combined with in vitro DNA binding assays

    PMID:11349150

    Open questions at the time
    • Human POT1 function not yet tested genetically
    • No structural information on the binding mode
    • Connection to the rest of the telomere complex unknown
  2. 2003 High

    How POT1 connects to the duplex telomeric DNA machinery and controls telomere length was resolved by demonstrating that POT1 is recruited through TRF1 and acts as the terminal transducer of TRF1-mediated telomere length regulation, with its DNA-binding domain required for this control.

    Evidence Co-immunoprecipitation, dominant-negative POT1 mutant overexpression, and telomere length analysis in human cells

    PMID:12768206 PMID:12781132

    Open questions at the time
    • Direct bridging partner between TRF1 and POT1 not yet identified
    • Mechanism of telomerase regulation not distinguished between access control and catalytic modulation
  3. 2003 High

    The structural basis of telomeric ssDNA recognition was established when crystal structures of the OB fold bound to telomeric DNA revealed sequence-specific contacts through base-stacking and unusual G-T base pairs, explaining why any sequence change disrupts binding.

    Evidence X-ray crystallography of S. pombe Pot1p N-terminal OB fold at 1.9 Å and human POT1 at 1.73 Å

    PMID:14614509 PMID:15558049

    Open questions at the time
    • C-terminal structure unknown
    • How POT1 engages the full-length overhang in the context of shelterin not resolved
  4. 2004 High

    The missing link between POT1 and the shelterin complex was identified as TPP1 (PIP1/PTOP), which binds the POT1 C-terminus and tethers it via TIN2 to TRF1, with loss of this bridge causing telomere elongation.

    Evidence Mass spectrometry identification, reciprocal Co-IP, shRNA/RNAi knockdown, telomere length analysis

    PMID:15181449 PMID:15231715

    Open questions at the time
    • Structure of POT1-TPP1 interface not yet determined
    • Whether TPP1 modulates POT1 DNA-binding affinity unknown
  5. 2005 High

    The paradox of POT1 being both a positive and negative regulator of telomerase was resolved by showing that its position on ssDNA determines outcome: 3'-terminal binding blocks telomerase access, while internal binding creates a preferred substrate that enhances processivity; POT1 also resolves G-quadruplexes to permit extension.

    Evidence In vitro telomerase assays with positionally defined POT1-DNA substrates, G-quadruplex unfolding assays

    PMID:15632080 PMID:15792951 PMID:16043710

    Open questions at the time
    • Regulation of POT1 positioning in vivo not determined
    • How G-quadruplex resolution is coordinated with telomerase extension in cells unknown
  6. 2005 High

    POT1's role beyond end-capping was expanded to include stimulation of WRN/BLM RecQ helicases at telomeric substrates and determination of the precise 5'-end sequence of the chromosome, establishing POT1 as a coordinator of telomere processing.

    Evidence In vitro helicase stimulation assays, RNAi-mediated POT1 depletion with 5'-end sequencing and overhang analysis

    PMID:15973431 PMID:16030011

    Open questions at the time
    • Whether POT1-helicase cooperation occurs at replication forks or only during end processing not distinguished
    • Mechanism of 5'-end specification not structurally resolved
  7. 2006 High

    Conditional knockout of mouse Pot1 paralogs definitively separated ATR-suppression (Pot1a) from C-strand processing (Pot1b) functions, and demonstrated that POT1 loss triggers ATR-dependent senescence, telomere elongation, and aberrant recombination.

    Evidence Conditional knockout mice for Pot1a and Pot1b with complementation, epistasis with NBS1 and p53

    PMID:16839876 PMID:16839877

    Open questions at the time
    • Human POT1 is a single gene—how it performs both functions simultaneously not yet explained
    • Domain determinants specifying each function not mapped
  8. 2007 High

    The shelterin end-protection paradigm was clarified: TRF2 suppresses ATM while POT1 independently suppresses ATR, and the TPP1-POT1 heterodimer enhances POT1 DNA-binding affinity and is essential for both telomere protection and telomerase regulation.

    Evidence Genetic epistasis with conditional TRF2/POT1 deletions in ATM/ATR-null backgrounds; TPP1-POT1 binding and telomerase recruitment assays

    PMID:17237767 PMID:17632522 PMID:17687332

    Open questions at the time
    • Structural basis of POT1-mediated ATR exclusion not visualized
    • Whether POT1 directly contacts ATR pathway components unknown
  9. 2009 High

    POT1's ability to discriminate telomeric DNA from the TERRA RNA transcript was explained by a single thymidine residue whose 2'-H is buried in a hydrophobic pocket (Phe62), with TPP1 augmenting this selectivity.

    Evidence Crystal structure of POT1 with ribouridine-substituted substrate, F62Y mutagenesis, binding assays

    PMID:20080730

    Open questions at the time
    • Whether this discrimination is relevant in vivo where TERRA is present at telomeres not tested
    • POT1-TERRA functional interplay not characterized
  10. 2010 High

    The mechanism by which POT1-TPP1 enhances telomerase processivity was defined as slowing primer dissociation and aiding translocation, with a single heterodimer sufficient for the effect.

    Evidence In vitro telomerase processivity and dissociation rate measurements with purified POT1-TPP1

    PMID:20094033

    Open questions at the time
    • Structural visualization of the telomerase-POT1-TPP1-DNA complex not yet achieved
    • Whether multiple POT1-TPP1 units cooperate during processive extension unknown
  11. 2011 High

    The cell-cycle-regulated RPA-to-POT1 switch mechanism was elucidated: hnRNPA1 displaces RPA but not POT1 from telomeric ssDNA, with TERRA controlling hnRNPA1 availability across S phase, and TIN2 stabilizing POT1-TPP1 to prevent RPA re-accumulation.

    Evidence Purified protein displacement assays, ChIP, RNAi, conditional TIN2 deletion with complementation

    PMID:21399625 PMID:22099311

    Open questions at the time
    • Kinetic parameters of the switch in vivo not measured
    • Additional post-translational modifications regulating the switch not fully catalogued
  12. 2015 High

    DNA-PKcs was identified as the kinase that phosphorylates hnRNP-A1 during G2/M to promote the RPA-to-POT1 switch, linking DNA damage kinase signaling to telomere protection timing.

    Evidence In vitro kinase assay, phosphomutant complementation, telomere fragility assays

    PMID:25999341

    Open questions at the time
    • Whether DNA-PKcs directly phosphorylates POT1 itself not examined
    • Upstream signals activating DNA-PKcs at telomeres not identified
  13. 2016 High

    A direct link between POT1 dysfunction and human disease was established when the S322L mutation was shown to cause Coats plus syndrome through defective C-strand fill-in requiring POT1/CST cooperation, and POT1 mutations in cancer were linked to ATR-dependent proliferative advantages.

    Evidence Patient-derived mutation analysis with complementation assays; mouse conditional KO in lymphoid progenitors with human CTCL mutations

    PMID:27013236 PMID:27239034

    Open questions at the time
    • Full spectrum of disease-causing POT1 mutations not catalogued
    • Whether all cancer-associated mutations act through the same mechanism not determined
  14. 2017 High

    The structural basis of the POT1 C-terminus was revealed as a third OB fold and a Holliday junction resolvase-like domain forming a V-shaped TPP1-binding platform, with cancer mutations disrupting this interface to cause POT1 instability and failure to suppress DDR.

    Evidence X-ray crystallography of POT1C-TPP1, mutagenesis, telomere dysfunction assays

    PMID:28393830 PMID:28393832

    Open questions at the time
    • Full-length POT1-TPP1 structure not yet obtained
    • Whether the resolvase-like domain has catalytic activity unknown
  15. 2020 High

    Quantitative biophysical analysis established that POT1 unfolds G-quadruplexes by conformational selection rather than induced fit, binding single-stranded conformers four orders of magnitude faster than folded G4, and POT1 loss in human cells triggers HDR-dependent telomeric defects including branched DNA and R-loops.

    Evidence Stopped-flow kinetics with multiple biophysical methods; conditional POT1 deletion with ChIP-MS and HDR-factor epistasis

    PMID:32232414 PMID:33073402

    Open questions at the time
    • Whether G-quadruplex conformational dynamics are rate-limiting for telomerase in vivo not tested
    • Identity of the HDR nucleases acting at POT1-depleted telomeres not fully resolved
  16. 2020 High

    POT1 dysfunction-induced replication stress was shown to trigger nuclear F-actin-mediated telomere relocalization to the nuclear periphery, where NPC components resolve replication defects—a previously unknown spatial quality control mechanism.

    Evidence CRISPRi screening, proximity labeling proteomics, NPC subunit depletion with telomere fragility assays

    PMID:33122293

    Open questions at the time
    • Which NPC subunits directly resolve the replication stress not identified
    • Whether this pathway operates at non-telomeric replication stress sites unknown
  17. 2022 High

    Cryo-EM structures of the telomerase-TPP1-POT1 holoenzyme revealed the physical basis of processivity enhancement, showing an unexpected DNA exit path and anchor site stabilized by POT1-TPP1 presence.

    Evidence Cryo-EM at 3.2–3.9 Å resolution

    PMID:35201900

    Open questions at the time
    • Dynamics of POT1-TPP1 repositioning during successive translocation cycles not captured
    • Structure of the complex with a full-length telomeric substrate not obtained
  18. 2023 High

    How POT1 protects the vulnerable ds/ss DNA junction was solved: a 'POT-hole' surface on the first OB fold recognizes the phosphorylated 5' end of the C-strand, and mutations in this surface compromise junction protection and DDR suppression.

    Evidence Crystal structures of POT1 with 5'-phosphorylated junction substrates, mutagenesis, telomere DDR assays

    PMID:37590346

    Open questions at the time
    • Whether POT-hole occupancy is regulated during the cell cycle not tested
    • How POT-hole recognition coordinates with TRF2-mediated t-loop formation unknown
  19. 2024 High

    The mechanism coupling G-strand extension to C-strand fill-in was resolved structurally: phosphorylated POT1 recruits CST-Polα/primase via its hinge region and holds the complex autoinhibited; dephosphorylation releases CST-Polα/primase for C-strand synthesis.

    Evidence Cryo-EM structures of POT1/TPP1-CST-Polα/primase complex, phosphorylation-dependent biochemical assays

    PMID:38838667

    Open questions at the time
    • Identity of the phosphatase that triggers CST release not determined
    • Timing of dephosphorylation relative to telomerase dissociation not established in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the phosphatase controlling CST release from POT1, the full-length structure of the complete shelterin–telomerase–CST assembly on a physiological substrate, and whether the resolvase-like domain of POT1C has catalytic activity.
  • No phosphatase identified for POT1 dephosphorylation
  • No full-length shelterin-telomerase-CST structural model
  • Catalytic potential of POT1C resolvase-like domain untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 8 GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0000228 nuclear chromosome 6 GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-69306 DNA Replication 3 R-HSA-1640170 Cell Cycle 2
Partners
BLMCSTTERTTIN2TPP1TRF1TRF2WRN
Complex memberships
POT1-TPP1 heterodimerPOT1-TPP1-CST-Polα/primaseShelterin (TRF1-TRF2-TIN2-TPP1-POT1-RAP1)

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 POT1 (protection of telomeres 1) binds the single-stranded G-rich telomeric DNA overhang. Deletion of fission yeast pot1+ causes immediate loss of telomeric DNA and chromosome circularization, establishing POT1 as essential for chromosome end protection. Genetic deletion in S. pombe, in vitro DNA binding assays Science High 11349150
2003 Human POT1 is recruited to telomeres through the TRF1 complex and controls telomerase-mediated telomere elongation. A POT1 mutant lacking its DNA-binding domain abrogated TRF1-mediated telomere length control and induced rapid telomere elongation, identifying POT1 as the terminal transducer of TRF1 telomere length signaling. Co-immunoprecipitation, dominant-negative mutant overexpression, telomere length analysis, EMSA Nature High 12768206
2003 Crystal structure of the N-terminal OB fold of S. pombe Pot1p bound to single-stranded telomeric DNA at 1.9 Å reveals sequence-specific binding through DNA self-recognition involving base-stacking and unusual G-T base pairs; any sequence change disrupts binding. X-ray crystallography, in vitro binding assays Nature High 14614509
2003 Human POT1 overexpression facilitates telomerase-dependent telomere elongation; all three splice variants extended telomeres in telomerase-positive cells but not in telomerase-negative cells, establishing POT1 as a positive regulator of telomerase-mediated telomere extension. Overexpression of splice variants, telomere length analysis (Southern blot), telomerase activity assays Current Biology High 12781132
2004 Crystal structure of human POT1 N-terminal half bound to telomeric ssDNA decamer (TTAGGGTTAG) at 1.73 Å reveals two OB folds: the first binds the initial six nucleotides and the second binds and protects the 3' end of ssDNA. X-ray crystallography, in vitro binding assays Nature Structural & Molecular Biology High 15558049
2004 POT1 minimal binding site is the telomeric nonamer 5'-TAGGGTTAG-3'; the OB fold is required for DNA binding; POT1 can bind both the 3' overhang and internally displaced TTAGGG repeats at the t-loop base. In vitro binding assays (EMSA, filter binding), deletion mutagenesis Journal of Biological Chemistry High 14715659
2004 PIP1 (later named TPP1) was identified by mass spectrometry as a POT1-interacting protein that also binds TIN2, tethering POT1 to the TRF1 complex. shRNA reduction of PIP1 or POT1 leads to telomere elongation. Mass spectrometry, co-immunoprecipitation, shRNA knockdown, telomere length analysis Genes & Development High 15231715
2004 PTOP (TPP1) interacts with the C-terminus of POT1 and recruits POT1 to telomeres. RNAi inhibition of PTOP or disruption of the PTOP-POT1 interaction prevents telomeric localization of POT1 and extends telomere length. Co-immunoprecipitation, RNAi knockdown, fluorescence microscopy, telomere length analysis Nature Cell Biology High 15181449
2004 Cooperative binding of S. pombe Pot1pN to single-stranded telomeric DNA: each monomer binds one hexanucleotide (GGTTAC); binding is cooperative with 3' end preference, suggesting Pot1 anchors at the chromosome 3' end and coats the entire single-stranded overhang. Gel filtration chromatography, filter-binding assay, in vitro binding kinetics Biochemistry High 12463756
2005 POT1 inhibits telomerase activity in vitro through its DNA-binding activity; POT1 is incapable of inhibiting telomerase on primers defective for POT1 binding, indicating that substrate access blockade is the inhibitory mechanism. In vitro telomerase activity assay, DNA binding mutants Molecular and Cellular Biology High 15632080
2005 POT1 disrupts telomeric G-quadruplex structures by forming a stoichiometric complex with the DNA, freeing the 3' tail and restoring processive elongation by telomerase in vitro. In vitro telomerase extension assays, G-quadruplex biochemical analyses PNAS High 16043710
2005 Depending on its position relative to the DNA 3' end, hPOT1 can either inhibit telomerase action (when bound at the 3' end) or form a preferred substrate for telomerase with improved activity and processivity (when bound one repeat before the 3' end, leaving an 8-nt tail). In vitro telomerase assay with recombinant POT1 and crystal structure-guided design Journal of Biological Chemistry High 15792951
2005 POT1 stimulates WRN and BLM helicases to unwind long telomeric forked duplexes and D-loops in a telomeric sequence-dependent manner. POT1 binds directly to WRN and BLM in vitro, and this cooperation requires telomeric sequence in the duplex region. In vitro helicase assays, direct protein binding (pulldown), HeLa nuclear extract co-precipitation Journal of Biological Chemistry High 16030011
2005 RNAi-mediated reduction of POT1 reduces 3' overhang DNA and causes transient DNA damage response at all telomeres in G1, but does not cause fusions or cell cycle arrest. POT1 also determines the 5'-end sequence of the telomere (normally ending ATC-5'), establishing POT1's role in defining chromosome end structure. RNAi knockdown, telomere overhang assays, cytogenetics, DNA damage marker staining The EMBO Journal High 15973431
2006 Conditional deletion of mouse Pot1a elicits ATR-dependent DNA damage response at telomeres, p53-dependent replicative senescence, telomere elongation, 3' overhang elongation, aberrant homologous recombination (telomere sister chromatid exchanges, telomere circles), and NBS1-dependent telomeric HR. Conditional knockout mouse, telomere FISH, CO-FISH, immunofluorescence, genetic epistasis with NBS1 Cell High 16839876
2006 Mouse has two POT1 paralogs with distinct functions: POT1a represses DNA damage signaling at telomeres (ATR pathway), whereas POT1b regulates the amount of single-stranded DNA at the telomere terminus (C-strand processing), as demonstrated by conditional knockouts and complementation. Conditional knockout mouse, complementation experiments, telomere overhang assays, DNA damage marker analysis Cell High 16839877
2007 TRF2 represses ATM kinase signaling at telomeres, while POT1 independently prevents activation of ATR kinase signaling. These two shelterin proteins act independently to suppress two distinct DNA damage response pathways. Conditional deletion of TRF2 and/or POT1 in ATM/ATR-deficient cell backgrounds, epistasis analysis Nature High 17687332
2007 TPP1 (a TEBP-beta homologue) forms a heterodimer with POT1, enhancing POT1 affinity for telomeric ssDNA. TPP1 OB fold and POT1-TPP1 binding are critical for telomere-length control and end protection. TPP1 physically associates with telomerase, providing a link between telomerase and the shelterin complex. Co-immunoprecipitation, in vitro binding assays, RNAi, telomere length analysis, pulldown with telomerase Nature High 17237767
2007 Mammalian Pot1 protective function requires interaction with Tpp1; Pot1 variants that cannot bind Tpp1 fail to protect telomeres even when they can bind ssDNA, as shown by complementation of Pot1 knockout mouse cells. Conditional knockout, RNAi, complementation with Pot1/POT1 mutants defective in Tpp1 binding Nature Structural & Molecular Biology High 17632522
2008 Fission yeast Tpz1 (TPP1 homolog) forms a complex with Pot1 that recruits effector molecules Ccq1 (positive telomerase regulator) and Poz1 (negative regulator bridging Pot1-Tpz1 to Taz1-Rap1), connecting single-stranded and double-stranded telomeric DNA regions. Co-immunoprecipitation, genetic analysis, telomere length assays in S. pombe Science High 18535244
2008 Domain-swap analysis of POT1a and POT1b shows that the DNA-binding domain of POT1a specifies ATR repression; a region between aa 300-350 of POT1b (outside the TPP1-binding domain) is required for C-strand resection control; human POT1 DNA-binding domain can replace POT1a's to repress ATR. Domain swapping, complementation in conditional knockout cells, telomere assays Molecular and Cellular Biology High 18955498
2009 A single deoxythymidine residue in a telomeric repeat dictates DNA vs. RNA discrimination by human POT1 and mouse POT1A. Crystal structure of hPOT1 with ribouridine shows the 2'-OH is buried in a hydrophobic region (Phe62), eliminating favorable H-bonding; TPP1 greatly augments this RNA discrimination. Binding studies, X-ray crystallography, mutagenesis (F62Y) PNAS High 20080730
2010 POT1-TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. A single POT1-TPP1-DNA interaction is necessary and sufficient. The effect is specific (gp32 cannot substitute) and consistent with a recruitment function. In vitro telomerase processivity assays, dissociation rate measurements, primer binding assays The EMBO Journal High 20094033
2011 hnRNPA1 displaces RPA (but not POT1) from telomeric ssDNA, facilitating an RPA-to-POT1 switch after replication. TERRA inhibits hnRNPA1 in early S phase, then declines in late S phase allowing hnRNPA1 activity; TERRA also promotes POT1 binding by removing hnRNPA1. Purified protein binding assays, cell extract fractionation, ChIP, RNA interference Nature High 21399625
2011 TIN2 is required for telomeric accumulation of TPP1/POT1a and POT1b. Upon TIN2 deletion, telomeres lose TPP1/POT1a, accumulate RPA, and elicit ATR signaling with all phenotypes of POT1a/b deletion, establishing that TIN2 tethering stabilizes TPP1/POT1 on ssDNA to exclude RPA. Conditional TIN2 deletion, complementation with TIN2 mutants, co-immunoprecipitation, telomere ChIP, ATR signaling readouts Molecular Cell High 22099311
2011 Multiple POT1-TPP1 heterodimers coat and compact long telomeric ssDNA (72-144 nt) into ordered nucleoprotein structures, as visualized by electron microscopy. EMSA, size-exclusion chromatography, electron microscopy Journal of Molecular Biology Medium 21596049
2012 POT1 binds stably to folded telomeric G-quadruplex DNA sequentially from 3' to 5', unfolding the G-quadruplex stepwise. The POT1-TPP1 complex induces continuous folding-unfolding cycles and slides back and forth on telomeric DNA. Single-molecule FRET Structure High 22981946
2012 POT1, TRF1, and TRF2 each enhance individual steps of long-patch base excision repair (LP-BER) and stimulate the complete reconstituted LP-BER pathway in vitro, suggesting telomere proteins evolved to allow selective DNA repair access at telomeres. Reconstituted LP-BER pathway assay with purified proteins Cell Cycle Medium 22336916
2014 TRF1 deploys TPP1/POT1 heterodimers through TIN2 to prevent ATR kinase activation during telomere replication and repress sister telomere associations; BLM helicase is separately recruited by TRF1 for lagging strand synthesis. These are two mechanistically distinct functions of TRF1. Mouse conditional knockouts (BLM, TRF1, TPP1, Rap1), TRF1/TIN2 mutant expression, epistasis Genes & Development High 25344324
2014 G-quadruplex formation at telomeric overhangs enhances POT1/TPP1 protection against RPA binding by two orders of magnitude (in K+ but not Na+ buffer). POT1 stably loads adjacent to a folded GQ, then unfolds the antiparallel form while parallel conformation remains folded. Single-molecule FRET with purified proteins PNAS High 24516170
2015 DNA-PKcs phosphorylates hnRNP-A1 during G2/M phases, promoting the RPA-to-POT1 switch on telomeric ssDNA. Loss of DNA-PKcs or hnRNP-A1 phosphorylation impairs this switch, causing telomeric DNA damage response during mitosis and fragile telomeres. In vitro kinase assay, phosphomutant complementation, ChIP, immunofluorescence Nucleic Acids Research High 25999341
2016 A POT1 S322L mutation (POT1-CP) causes Coats plus syndrome by being defective in regulating telomerase (causing elongation) and in maintaining the telomeric C-strand, resulting in extended 3' overhangs and stochastic telomere truncations; POT1/CST-dependent fill-in synthesis is required for C-strand maintenance. Patient-derived mutation analysis, cell proliferation assays, telomere length/overhang assays, complementation Genes & Development High 27013236
2016 POT1a depletion in common lymphoid progenitor cells combined with p53 deficiency induces ATR-dependent DNA damage signaling, telomere fragility, replication fork stalling, telomere elongation, and impaired CST function at telomeres; proliferation of POT1-deficient cancer cells requires attenuation of the ATR pathway. Mouse conditional KO, human cell CTCL patient mutations, ATR inhibition, replication stress assays Cell Reports High 27239034
2017 Crystal structure of POT1 C-terminus (POT1C) with TPP1 reveals POT1C has a bilobal structure with an OB fold and Holliday junction resolvase domain. Cancer-associated mutations partially disrupt the POT1-TPP1 complex, impairing telomeric DNA binding, leading to longer and fragile telomeres. X-ray crystallography, biochemical binding assays, functional cell-based assays Nature Communications High 28393830
2017 Crystal structure of POT1C with the POT1-binding motif of TPP1 shows POT1C contains a third OB fold and a Holliday junction resolvase-like domain adopting a V-shaped conformation. Cancer missense mutations disrupt POT1C-TPP1 interaction causing POT1 instability; POT1C mutants that retain TPP1 binding localize to telomeres but fail to repress DDR and A-NHEJ. X-ray crystallography, mutagenesis, Co-IP, telomere dysfunction assays Nature Communications High 28393832
2019 TSPYL5 prevents poly-ubiquitination and proteasomal degradation of POT1 exclusively in ALT+ cancer cells by inhibiting the deubiquitinase USP7. USP7 depletion rescues POT1 poly-ubiquitination; PML body association is required for this USP7/PML-triggered POT1 degradation pathway. Co-immunoprecipitation, ubiquitination assays, RNAi, proteasome inhibition, rescue experiments Molecular Cell High 31278054
2019 POT1 His266 residue is critical for telomere ssDNA length-dependent regulation of telomerase; CLL-associated H266L substitution reduces POT1-TPP1 binding to short ssDNA substrates and abolishes POT1-TPP1-mediated telomerase inhibition, leading to telomere overextension. Hydroxyl radical footprinting/mass spectrometry, in vitro telomerase assay, binding assays PNAS High 31685617
2019 TIN2 stimulates telomerase processivity in vitro in a manner dependent on the TPP1 TEL patch, establishing that TIN2/TPP1/POT1 is a functional shelterin subcomplex that together promotes telomerase processivity. Direct in vitro telomerase activity assays, telomere length analysis Molecular and Cellular Biology High 31383750
2020 POT1 unfolds telomeric G-quadruplexes by conformational selection: POT1 binds rapidly and tightly to single-stranded telomeric DNA but four orders of magnitude more slowly to folded G-quadruplex, with binding coupled to obligatory unfolding; 2 POT1 molecules bind per 24-nt G-quadruplex. Stopped-flow kinetics, fluorescence spectroscopy, isothermal calorimetry, analytical ultracentrifugation, molecular dynamics Nucleic Acids Research High 32232414
2020 Complete POT1 deletion in HEK293E cells causes rapid telomere elongation, length heterogeneity, branched telomeric DNA, telomeric R-loops, and telomere fragility. Homology-directed repair machinery drives these defects, as its inactivation suppresses POT1-loss-mediated telomeric DNA defects. Conditional gene deletion, telomere proteomics (ChIP-MS), genetic epistasis with HDR factors The EMBO Journal High 33073402
2020 Replication stress from POT1 dysfunction (mutant POT1 alleles) drives telomere relocalization to the nuclear periphery via nuclear F-actin polymerization; nuclear pore complex subunits resolve replication defects at these telomeres, and NPC depletion in POT1-mutant context increases telomere fragility and sister chromatid exchanges. CRISPR interference, biotin-based proximity labeling proteomics, imaging, NPC subunit depletion Genes & Development High 33122293
2021 Cancer-associated POT1 mutations in human ESCs and HSCs cause telomere elongation without inducing telomere damage responses, suggesting caPOT1 mutations are selected during cancer progression for their ability to elongate telomeres rather than through DNA damage signaling. CRISPR engineering of patient mutations, telomere length assays, DNA damage marker analysis, in vitro/in vivo competition The EMBO Journal High 33934394
2021 Mouse POT1b (independent of its CST function) enhances telomerase recruitment to telomeres through three specific amino acids in its TPP1-interacting C-terminus, while POT1a negatively regulates telomere length by inhibiting telomerase recruitment. Conditional mouse KO, complementation with POT1a/b chimeric mutants, telomere length analysis, telomerase ChIP Nature Communications High 34535663
2022 Cryo-EM structures of DNA-bound telomerase in complex with TPP1 (3.2 Å) and TPP1-POT1 (3.9 Å) reveal interactions crucial for telomerase recruitment to telomeres. TPP1-POT1 presence stabilizes DNA and reveals an unexpected DNA exit path from the telomerase active site and a DNA anchor site important for processivity. Cryo-EM structure determination Science High 35201900
2019 SerRS (seryl tRNA synthetase) directly binds telomeric DNA repeats and interacts with the OB1 domain of POT1, tethering more POT1 to telomeres, which prevents telomerase recruitment and leads to progressive telomere shortening. Co-immunoprecipitation, telomere ChIP, in vitro binding assays, telomere length analysis Signal Transduction and Targeted Therapy Medium 31815007
2023 Human POT1 protects the telomeric double-stranded/single-stranded DNA junction by recognizing the phosphorylated 5' end of the chromosome through a 'POT-hole' surface. Crystal structures reveal this mechanism; mutations in the POT-hole compromise junction protection and DDR suppression. Mouse POT1a (not POT1b) contains a POT-hole, explaining POT1a sufficiency for end protection. X-ray crystallography, mutagenesis, in vitro binding assays, telomere DDR assays in human cells Science High 37590346
2024 Cryo-EM structures of human CST bound to POT1/TPP1 reveal how CST is recruited to telomeres by POT1. POT1 hinge phosphorylation is required for CST recruitment; phosphorylated POT1 holds CST-Polα/primase in an autoinhibited state; dephosphorylation releases CST-Polα/primase to perform C-strand fill-in synthesis after telomerase has extended the G-strand. Cryo-EM structure determination, biochemical assays, phosphorylation analysis Cell High 38838667
2002 Human POT1 localizes to telomeres in interphase nuclei as demonstrated by immunofluorescence of epitope-tagged hPot1. Multiple splice variants exist with different abilities to form complexes with single-stranded telomeric DNA. Indirect immunofluorescence, EMSA, alternative splicing analysis Molecular and Cellular Biology High 12391173
2009 POT1 associates with TRF2; a full-length POT1 mutant defective in TRF2 association (but not TPP1 binding) induces telomere elongation; disruption of TRF2-POT1 association reduces the interaction of TRF2 with RAP1 and TIN2. Thus, POT1 association with both ssDNA and TRF2 is required for telomere length homeostasis. Co-immunoprecipitation, POT1 mutant complementation, telomere length analysis Molecular and Cellular Biology Medium 19651898
2013 C. elegans POT-1 anchors telomeres at the nuclear periphery through the NE protein SUN-1; targeted POT-1 is sufficient to anchor chromatin to the NE in a SUN-1-dependent manner. POT-1 localization to telomeres is independent of POT-2. Live imaging in C. elegans embryos, genetic knockouts, ectopic tethering Journal of Cell Biology Medium 24297748

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Pot1, the putative telomere end-binding protein in fission yeast and humans. Science (New York, N.Y.) 812 11349150
2007 Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 703 17687332
2003 POT1 as a terminal transducer of TRF1 telomere length control. Nature 547 12768206
2007 TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature 390 17237767
2004 Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nature structural & molecular biology 383 15558049
2004 POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes & development 353 15231715
2004 PTOP interacts with POT1 and regulates its localization to telomeres. Nature cell biology 349 15181449
2006 Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 331 16839876
2006 Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres. Cell 319 16839877
2014 POT1 loss-of-function variants predispose to familial melanoma. Nature genetics 317 24686849
2005 Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro. Proceedings of the National Academy of Sciences of the United States of America 315 16043710
2011 TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature 280 21399625
2014 Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nature genetics 277 24686846
2005 POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. The EMBO journal 240 15973431
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
2006 The G-quadruplex ligand telomestatin inhibits POT1 binding to telomeric sequences in vitro and induces GFP-POT1 dissociation from telomeres in human cells. Cancer research 170 16849533
2003 Human POT1 facilitates telomere elongation by telomerase. Current biology : CB 170 12781132
2003 DNA self-recognition in the structure of Pot1 bound to telomeric single-stranded DNA. Nature 168 14614509
2006 Telomestatin-induced telomere uncapping is modulated by POT1 through G-overhang extension in HT1080 human tumor cells. The Journal of biological chemistry 164 17050546
2005 Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Molecular and cellular biology 159 15632080
2005 POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates. The Journal of biological chemistry 157 16030011
2014 TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling. Genes & development 155 25344324
2007 Telomere protection by mammalian Pot1 requires interaction with Tpp1. Nature structural & molecular biology 152 17632522
2010 POT1-TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. The EMBO journal 143 20094033
2002 Human Pot1 (protection of telomeres) protein: cytolocalization, gene structure, and alternative splicing. Molecular and cellular biology 141 12391173
2015 A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families. Nature communications 138 26403419
2005 Switching human telomerase on and off with hPOT1 protein in vitro. The Journal of biological chemistry 134 15792951
2005 POT1 and TRF2 cooperate to maintain telomeric integrity. Molecular and cellular biology 131 15657433
2004 DNA binding features of human POT1: a nonamer 5'-TAGGGTTAG-3' minimal binding site, sequence specificity, and internal binding to multimeric sites. The Journal of biological chemistry 131 14715659
2014 G-quadruplex formation in telomeres enhances POT1/TPP1 protection against RPA binding. Proceedings of the National Academy of Sciences of the United States of America 120 24516170
2004 Loss of hPot1 function leads to telomere instability and a cut-like phenotype. Current biology : CB 119 15620654
2012 POT1-TPP1 regulates telomeric overhang structural dynamics. Structure (London, England : 1993) 108 22981946
2016 Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy. Blood 103 27226433
2005 The recessive potyvirus resistance gene pot-1 is the tomato orthologue of the pepper pvr2-eIF4E gene. Molecular genetics and genomics : MGG 103 15971038
2008 Functional dissection of human and mouse POT1 proteins. Molecular and cellular biology 101 18955498
2016 Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis. Cell reports 97 27239034
2004 Expression of POT1 is associated with tumor stage and telomere length in gastric carcinoma. Cancer research 93 14744765
2017 Structural and functional analysis of the human POT1-TPP1 telomeric complex. Nature communications 85 28393830
2017 Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nature communications 82 28393832
2016 A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus. Genes & development 82 27013236
2022 Structural basis of human telomerase recruitment by TPP1-POT1. Science (New York, N.Y.) 78 35201900
2007 Arabidopsis POT1 associates with the telomerase RNP and is required for telomere maintenance. The EMBO journal 77 17627276
2010 Single molecule studies of physiologically relevant telomeric tails reveal POT1 mechanism for promoting G-quadruplex unfolding. The Journal of biological chemistry 75 21183684
2002 Cooperative binding of single-stranded telomeric DNA by the Pot1 protein of Schizosaccharomyces pombe. Biochemistry 75 12463756
2017 The wide spectrum of POT1 gene variants correlates with multiple cancer types. European journal of human genetics : EJHG 69 28853721
2014 TRF2-tethered TIN2 can mediate telomere protection by TPP1/POT1. Molecular and cellular biology 68 24469404
2004 Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1. Molecular and cellular biology 64 15060173
2006 Vertebrate POT1 restricts G-overhang length and prevents activation of a telomeric DNA damage checkpoint but is dispensable for overhang protection. Molecular and cellular biology 59 16943437
2010 Pot1 and telomere maintenance. FEBS letters 56 20493859
2015 DNA-PKcs phosphorylates hnRNP-A1 to facilitate the RPA-to-POT1 switch and telomere capping after replication. Nucleic acids research 54 25999341
2007 Pot1 and cell cycle progression cooperate in telomere length regulation. Nature structural & molecular biology 54 18066078
2020 Replication stress conferred by POT1 dysfunction promotes telomere relocalization to the nuclear pore. Genes & development 52 33122293
2009 How telomeric protein POT1 avoids RNA to achieve specificity for single-stranded DNA. Proceedings of the National Academy of Sciences of the United States of America 52 20080730
2004 Prediction of multiple tandem OB-fold domains in telomere end-binding proteins Pot1 and Cdc13. Structure (London, England : 1993) 52 15458635
2016 Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis. Oncogene 50 27869160
2010 The protein network surrounding the human telomere repeat binding factors TRF1, TRF2, and POT1. PloS one 50 20811636
2020 Role of POT1 in Human Cancer. Cancers 49 32987645
2013 Cancer chromosomes going to POT1. Nature genetics 48 23619786
2009 Telomeric D-loops containing 8-oxo-2'-deoxyguanosine are preferred substrates for Werner and Bloom syndrome helicases and are bound by POT1. The Journal of biological chemistry 46 19734539
2021 Cancer-associated POT1 mutations lead to telomere elongation without induction of a DNA damage response. The EMBO journal 45 33934394
2019 TSPYL5 Depletion Induces Specific Death of ALT Cells through USP7-Dependent Proteasomal Degradation of POT1. Molecular cell 44 31278054
2020 POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families. Journal of medical genetics 43 31937561
2020 Human shelterin protein POT1 prevents severe telomere instability induced by homology-directed DNA repair. The EMBO journal 42 33073402
2005 Distinct requirements for Pot1 in limiting telomere length and maintaining chromosome stability. Molecular and cellular biology 42 15964812
2019 TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity. Molecular and cellular biology 41 31383750
2020 POT1-TPP1 telomere length regulation and disease. Computational and structural biotechnology journal 40 32774788
2020 A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer. Cancers 39 32492864
2013 The shelterin protein POT-1 anchors Caenorhabditis elegans telomeres through SUN-1 at the nuclear periphery. The Journal of cell biology 37 24297748
2012 Telomere proteins POT1, TRF1 and TRF2 augment long-patch base excision repair in vitro. Cell cycle (Georgetown, Tex.) 37 22336916
2020 Bacillus licheniformis strain POT1 mediated polyphenol biosynthetic pathways genes activation and systemic resistance in potato plants against Alfalfa mosaic virus. Scientific reports 36 32999301
2019 Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma. JAMA dermatology 36 30586141
2017 A new POT1 germline mutation-expanding the spectrum of POT1-associated cancers. Familial cancer 36 28389767
2020 Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1. Cancers 34 32325837
2011 Multiple POT1-TPP1 proteins coat and compact long telomeric single-stranded DNA. Journal of molecular biology 34 21596049
2005 Extended DNA binding site in Pot1 broadens sequence specificity to allow recognition of heterogeneous fission yeast telomeres. The Journal of biological chemistry 34 15637058
2021 Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres. Nature communications 33 34535663
2023 Human POT1 protects the telomeric ds-ss DNA junction by capping the 5' end of the chromosome. Science (New York, N.Y.) 32 37590346
2008 Distinct functions of POT1 at telomeres. Molecular and cellular biology 32 18519588
2010 Pot1 inactivation leads to rampant telomere resection and loss in one cell cycle. Nucleic acids research 31 20601686
2020 Human POT1 unfolds G-quadruplexes by conformational selection. Nucleic acids research 30 32232414
2018 Investigation of deleterious effects of nsSNPs in the POT1 gene: a structural genomics-based approach to understand the mechanism of cancer development. Journal of cellular biochemistry 30 30556179
2008 Mechanism and substrate specificity of telomeric protein POT1 stimulation of the Werner syndrome helicase. Nucleic acids research 30 18583366
2022 Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis. The Journal of experimental medicine 29 35420632
2009 POT1 association with TRF2 regulates telomere length. Molecular and cellular biology 26 19651898
2012 RPA and POT1: friends or foes at telomeres? Cell cycle (Georgetown, Tex.) 25 22373525
2009 POT1-independent single-strand telomeric DNA binding activities in Brassicaceae. The Plant journal : for cell and molecular biology 25 19228335
1992 The POT1 gene for yeast peroxisomal thiolase is subject to three different mechanisms of regulation. Molecular microbiology 25 1354832
2020 Genetic variation in POT1 and risk of thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study. PloS one 24 32040538
2020 MiR-185 targets POT1 to induce telomere dysfunction and cellular senescence. Aging 24 32687062
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 24 31685617
2017 The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age. Nature communications 24 28986560
2019 Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence. Signal transduction and targeted therapy 23 31815007
2013 Caenorhabditis elegans POT-1 and POT-2 repress telomere maintenance pathways. G3 (Bethesda, Md.) 23 23390606
2011 DNA-induced dimerization of the single-stranded DNA binding telomeric protein Pot1 from Schizosaccharomyces pombe. Nucleic acids research 23 21911358
2016 POT1-TPP1 Binding and Unfolding of Telomere DNA Discriminates against Structural Polymorphism. Journal of molecular biology 22 27173378
2024 POT1 recruits and regulates CST-Polα/primase at human telomeres. Cell 20 38838667
2017 POT1-mediated δ-integration strategy for high-copy, stable expression of heterologous proteins in Saccharomyces cerevisiae. FEMS yeast research 20 28922845
2005 Alternative splicing of Pot1 (Protection of telomere)-like genes in Arabidopsis thaliana. Genes & genetic systems 20 15824455
2012 Interaction of Berberine derivative with protein POT1 affect telomere function in cancer cells. Biochemical and biophysical research communications 19 22369941