Telomere Maintenance (Homo sapiens)

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1, 3, 8, 9, 12...7, 21921294-6, 14, 17...109239209nucleoplasmPOLE4 POLD2 POLD1 POLA1 TERF2IP POLE3 HIST1H2AD Processive complexloaded ontelomere:nicked DNAfrom adjacentOkazaki fragmentsTERF2IP HIST1H2BC Processive complexloaded ontelomere:Okazakifragment:FlapG-strand chromosomeend - TelomericNucleosomeACD POLA2 HIST3H2BB adenosine5'-monophosphateHIST1H2AC POLD1 HIST1H2BN G-strand Chromosome end with an additional single strand repeat - Telomeric HIST1H2BN ATP RFC2 POLD4 TelomeraseHoloenzymeBase-paired to theTelomericChromosome End withan Additionalsingle StrandedTelomere repeatDKC1 PCNA TERF2 DNA primer HIST1H2BK cytidine5'-monophosphateHIST2H2BE ligated C-strand Okazaki fragment H2AFB1 Flap RPA1 ligated C-strand Okazaki fragment ATPRPA1 G-strand Chromosome end with two additional single strand repeats - Telomeric POLA2 HIST2H2AC Processive complexloaded ontelomere:Okazakifragment complexCTP RFC HeteropentamerHIST1H4 NHP2POLD2 POLD3 RNA primer POLA1 POLD2 TINF2 HIST3H3 POLD4 HIST1H2AB H2AFX Extended AndProcessed TelomereEnd and AssociatedDNA Binding andPackaging ProteinComplexShelterin complexG-strand Chromosome end with an additional single strand repeat - Telomeric GTP HIST1H2BD HIST2H2AA3 RFC5 HIST1H2BJ Processive complexloaded ontelomere:Okazakifragment:Flap:RPAheterotrimerG-strand Chromosome end with two additional single strand repeats - Telomeric TERF1 HIST1H2BH RFC1 PCNA Telomerase RNA Component (TERC) HIST1H2BH POLD3 G-strand Chromosomeend with twoadditional singlestrand repeats -TelomericH2BFS HIST2H2AC DNA polymerasealpha:primaseligated C-strand Okazaki fragment PRIM2 G-strand Chromosome end with two additional single strand repeats - Telomeric G-strand chromosome end - Telomeric HIST1H2BN POT1POLD4 HIST1H2BK HIST1H2BM TERF1 C-strand Okazaki fragment H2AFV ADPPRIM1 POLD1 POLD4 Processive complexloaded ontelomere:Okazakifragments:RemainingFlapG-strand Chromosome end with two additional single strand repeats - Telomeric HIST2H2AC PCNA G-strand Chromosome end with two additional single strand repeats - Telomeric POLD1 DNA primer POLD1 POLD4 C-strand Okazaki fragment PCNA DNA primer RNA primer HIST1H2BO POLD3 HIST1H2BA HIST1H2BB POLE4 POLE3 H2AFV TERF2IP HIST1H2AD POLE UTP DNA primer H2AFJ HIST2H2AA3 G-strand Chromosome end with two additional single strand repeats - Telomeric TERT G-strand chromosome end - Telomeric RFC4 Telomerase RNA Component (TERC) PRIM2 TERT G-strand Chromosome end with two additional single strand repeats - Telomeric POLD3 POLD2 NTPExtended AndProcessed TelomereEnd and AssociatedDNA Binding andPackaging ProteinComplex Folded IntoHigher OrderStructurePOLD3 RFC3 TelomeraseHoloenzyme:Telomeric RNP End with Two Additional Single Stranded Telomere RepeatsPOLD3 Telomerase RNP Boundand base-paired tothe TelomericChromosome EndRNA primer-DNAprimer:G-strandextendedtelomere:PCNAFlap Telomerase RNAComponent (TERC)G-strand Chromosome end with two additional single strand repeats - Telomeric HIST3H3 POLE POLD2 HIST2H2AA3 HIST1H2BM RNA primer-DNAprimer:G-strandextended telomereH2AFX PRIM1 POLD3 HIST1H2BK HIST1H2BC RFC3 RFC1 RNA primer:G-strandextended telomereend:DNA polymerasealpha:primasecomplexPOLA1 dGTPH2AFZ PCNA H2BFS PRIM2 Telomerase RNA Component (TERC) dTTPExtended AndProcessed TelomereEndG-strand Chromosome end with two additional single strand repeats - Telomeric DKC1 POT1 HIST1H2BL PCNA TERF2 H2AFV RPA2 RNA primer C-strand Okazaki fragment TERT HIST1H2BH ACD POLD1 POLA2 uridine5'-monophosphatePOLD3 TERF1 RFC5 DNA polymerasealpha:primase:DNApolymerasealpha:G-strandextended telomereendPOLD2 HIST1H4 PRIM1 G-strand Chromosome end with two additional single strand repeats and a subterminal loop - Telomeric POLD4 G-strand Chromosome end with two additional single strand repeats - Telomeric Telomerase RNA Component (TERC) RPA heterotrimerPRIM2 Telomerase RNA Component (TERC) HIST1H2AJ dATPRPA3 HIST1H2AC RFC2 G-strand Chromosome end with two additional single strand repeats - Telomeric RPA2 TERT HIST1H2BD PCNA RUVBL2HIST1H2BL TINF2 H2AFJ DKC1 POLD3 DNA polymeraseepsilonC-strand Okazaki fragment G-strand Chromosome end with two additional single strand repeats - Telomeric POLD4 POLD4 HIST1H2BA C-strand Okazaki fragment minus Flap ACD RPA2 RPA1 TERT RNA primer RFC1 H2BFS Telomerase RNPDKC1 LIG1PCNA homotrimerPRIM1 POLE2 DKC1 HIST1H2AD RPA3 H2AFB1 POLD4 POT1 HIST1H2BO POLD1 POLE2 Telomerase RNA Component (TERC) POLD1 G-strand Chromosome end with two additional single strand repeats - Telomeric TERTTINF2 H2AFB1 Processive complexloaded on telomereRPA3 RFCHeteropentamer:RNAprimer-DNAprimer:G-strandextended telomereend duplex:PCNAhomotrimerHIST1H4 POLD2 PCNA HIST1H2BJ HIST2H2BE HIST1H2AJ HIST2H2BE DKC1 HIST1H2BA RNA primer PCNA HIST1H2AC HIST1H2BL H2AFJ DNA2POLA2 RFC5 DNA primer PCNA TERT HIST3H3 Processive complexloaded ontelomere:Okazakifragment:Flap:RPAheterotrimer:dna2RFC4 H2AFZ RFC3 TelomeraseRNP:TelomericChromosome End withan Additionalsingle StrandedTelomere repeatPOLD1 POLD2 dCTPPOLD2 POLA1 HIST1H2BD C-strand Okazaki fragment RFC2 H2AFZ Processive complexloaded ontelomere:ligatedC-strand OkazakifragmentsPOT1 HIST3H2BB G-strand Chromosome end with two additional single strand repeats - Telomeric WRAP53HIST1H2AB HIST1H2BO Remaining Flap ligated C-strand Okazaki fragment RFC4 HIST1H2BB DNA2 Telomerase RNP Boundto the TelomericChromosome EndRUVBL1H2AFX HIST1H2BM FEN1DKC1HIST1H2BJ TERF2 HIST1H2AJ RNA primer HIST1H2BB HIST1H2BC RNA primer HIST3H2BB G-strand Chromosome end with two additional single strand repeats - Telomeric Flap RFCHeteropentamer:RNAprimer-DNAprimer:G-strandextended telomereendDNA Polymerase deltatetramerG-strand Chromosome end with two additional single strand repeats - Telomeric guanosine5'-monophosphatePCNA HIST1H2AB 1113, 164


Description

Telomeres are protein-DNA complexes at the ends of linear chromosomes that are important for genome stability. Telomeric DNA in humans, as in many eukaryotic organisms, consists of tandem repeats (Blackburn and Gall 1978; Moyzis et al. 1988; Meyne et al. 1989). The repeats at human telomeres are composed of TTAGGG sequences and stretch for several kilobase pairs. Another feature of telomeric DNA in many eukaryotes is a G-rich 3' single strand overhang, which in humans is estimated to be approximately 50-300 bases long (Makarov et al. 1997; Wright et al. 1997; Huffman et al. 2000). Telomeric DNA isolated from humans and several other organisms can form a lasso-type structure called a t-loop in which the 3' single-strand end is presumed to invade the double stranded telomeric DNA repeat tract (Griffith et al. 1999). Telomeric DNA is bound by multiple protein factors that play important roles in regulating telomere length and in protecting the chromosome end from recombination, non-homologous end-joining, DNA damage signaling, and unregulated nucleolytic attack (reviewed in de Lange 2005).


DNA attrition can occur at telomeres, which can impact cell viability. Attrition can occur owing to the "end-replication problem", a consequence of the mechanism of lagging-strand synthesis (Watson 1972; Olovnikov 1973). Besides incomplete replication, nucleolytic processing also likely contributes to telomere attrition (Huffman et al. 2000). If telomeres become critically shortened, replicative senescence can result (Harley et al. 1990). Thus, in order to undergo multiple divisions, cells need a mechanism to replenish the sequence at their chromosome ends.


The primary means for maintaining the sequence at chromosome ends in many eukaryotic organisms, including humans, is based on telomerase (Greider and Blackburn, 1985; Morin 1989). Telomerase is a ribonucleoprotein complex minimally composed of a conserved protein subunit containing a reverse transcriptase domain (telomerase reverse transcriptase, TERT) (Lingner et al. 1997; Nakamura et al. 1997) and a template-containing RNA (telomerase RNA component, TERC, TR, TER) (Greider and Blackburn, 1987; Feng et al 1995). Telomerase uses the RNA template to direct addition of multiple tandem repeats to the 3' G-rich single strand overhang. Besides extension by telomerase, maintenance of telomeric DNA involves additional activities, including C-strand synthesis, which fills in the opposing strand, and nucleolytic processing, which likely contributes to the generation of the 3' overhang.
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Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 157579
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Blackburn, EH, Seidel, Jeff

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Ontology Terms

 

Bibliography

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  1. Olovnikov AM.; ''A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon.''; PubMed Europe PMC
  2. Dai X, Huang C, Bhusari A, Sampathi S, Schubert K, Chai W.; ''Molecular steps of G-overhang generation at human telomeres and its function in chromosome end protection.''; PubMed Europe PMC
  3. Greider CW, Blackburn EH.; ''A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis.''; PubMed Europe PMC
  4. Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ, Reddel RR.; ''Protein composition of catalytically active human telomerase from immortal cells.''; PubMed Europe PMC
  5. Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE.; ''Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly.''; PubMed Europe PMC
  6. Pogacić V, Dragon F, Filipowicz W.; ''Human H/ACA small nucleolar RNPs and telomerase share evolutionarily conserved proteins NHP2 and NOP10.''; PubMed Europe PMC
  7. Moldovan GL, Pfander B, Jentsch S.; ''PCNA, the maestro of the replication fork.''; PubMed Europe PMC
  8. Vega LR, Mateyak MK, Zakian VA.; ''Getting to the end: telomerase access in yeast and humans.''; PubMed Europe PMC
  9. Smogorzewska A, de Lange T.; ''Regulation of telomerase by telomeric proteins.''; PubMed Europe PMC
  10. Armbruster BN, Linardic CM, Veldman T, Bansal NP, Downie DL, Counter CM.; ''Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1.''; PubMed Europe PMC
  11. Hubscher U, Maga G, Spadari S.; ''Eukaryotic DNA polymerases.''; PubMed Europe PMC
  12. de Lange T.; ''Shelterin: the protein complex that shapes and safeguards human telomeres.''; PubMed Europe PMC
  13. Li Y, Pursell ZF, Linn S.; ''Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon.''; PubMed Europe PMC
  14. Venteicher AS, Abreu EB, Meng Z, McCann KE, Terns RM, Veenstra TD, Terns MP, Artandi SE.; ''A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis.''; PubMed Europe PMC
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  16. Li Y, Asahara H, Patel VS, Zhou S, Linn S.; ''Purification, cDNA cloning, and gene mapping of the small subunit of human DNA polymerase epsilon.''; PubMed Europe PMC
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  18. Snow BE, Erdmann N, Cruickshank J, Goldman H, Gill RM, Robinson MO, Harrington L.; ''Functional conservation of the telomerase protein Est1p in humans.''; PubMed Europe PMC
  19. Greider CW, Blackburn EH.; ''Identification of a specific telomere terminal transferase activity in Tetrahymena extracts.''; PubMed Europe PMC
  20. Murakami T, Takano R, Takeo S, Taniguchi R, Ogawa K, Ohashi E, Tsurimoto T.; ''Stable interaction between the human proliferating cell nuclear antigen loader complex Ctf18-replication factor C (RFC) and DNA polymerase {epsilon} is mediated by the cohesion-specific subunits, Ctf18, Dcc1, and Ctf8.''; PubMed Europe PMC
  21. Ohki R, Ishikawa F.; ''Telomere-bound TRF1 and TRF2 stall the replication fork at telomeric repeats.''; PubMed Europe PMC
  22. Watson JD.; ''Origin of concatemeric T7 DNA.''; PubMed Europe PMC
  23. Wang TS, Hu SZ, Korn D.; ''DNA primase from KB cells. Characterization of a primase activity tightly associated with immunoaffinity-purified DNA polymerase-alpha.''; PubMed Europe PMC
  24. Vulliamy T, Beswick R, Kirwan M, Marrone A, Digweed M, Walne A, Dokal I.; ''Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101284view11:17, 1 November 2018ReactomeTeamreactome version 66
100821view20:48, 31 October 2018ReactomeTeamreactome version 65
100362view19:23, 31 October 2018ReactomeTeamreactome version 64
99907view16:06, 31 October 2018ReactomeTeamreactome version 63
99463view14:38, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93874view13:42, 16 August 2017ReactomeTeamreactome version 61
93441view11:23, 9 August 2017ReactomeTeamreactome version 61
88407view11:43, 5 August 2016FehrhartOntology Term : 'pathway pertinent to DNA replication and repair, cell cycle, maintenance of genomic integrity, RNA and protein biosynthesis' added !
86532view09:20, 11 July 2016ReactomeTeamreactome version 56
83097view09:58, 18 November 2015ReactomeTeamVersion54
81422view12:57, 21 August 2015ReactomeTeamVersion53
76893view08:16, 17 July 2014ReactomeTeamFixed remaining interactions
76598view11:57, 16 July 2014ReactomeTeamFixed remaining interactions
75930view09:58, 11 June 2014ReactomeTeamRe-fixing comment source
75631view10:50, 10 June 2014ReactomeTeamReactome 48 Update
74986view13:50, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74630view08:41, 30 April 2014ReactomeTeamReactome46
68975view17:41, 8 July 2013MaintBotUpdated to 2013 gpml schema
42143view22:00, 4 March 2011MaintBotAutomatic update
39954view05:58, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ACD ProteinQ96AP0 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
C-strand Okazaki fragment R-ALL-176398 (Reactome)
C-strand Okazaki fragment minus Flap R-ALL-176397 (Reactome)
CTP MetaboliteCHEBI:17677 (ChEBI)
DKC1 ProteinO60832 (Uniprot-TrEMBL)
DKC1ProteinO60832 (Uniprot-TrEMBL)
DNA Polymerase delta tetramerComplexR-HSA-68450 (Reactome)
DNA polymerase

alpha:primase:DNA polymerase alpha:G-strand extended telomere

end
ComplexR-HSA-174473 (Reactome)
DNA polymerase alpha:primaseComplexR-HSA-68507 (Reactome)
DNA polymerase epsilonComplexR-HSA-68483 (Reactome)
DNA primer R-ALL-68424 (Reactome)
DNA2 ProteinP51530 (Uniprot-TrEMBL)
DNA2ProteinP51530 (Uniprot-TrEMBL)
Extended And

Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order

Structure
ComplexR-HSA-182751 (Reactome)
Extended And

Processed Telomere End and Associated DNA Binding and Packaging Protein

Complex
ComplexR-HSA-176703 (Reactome)
Extended And

Processed Telomere

End
ComplexR-ALL-176706 (Reactome)
FEN1ProteinP39748 (Uniprot-TrEMBL)
Flap R-ALL-68454 (Reactome)
G-strand Chromosome

end with two additional single strand repeats -

Telomeric
MetaboliteCHEBI:15986 (ChEBI)
G-strand Chromosome end with an additional single strand repeat - Telomeric MetaboliteCHEBI:15986 (ChEBI)
G-strand Chromosome end with two additional single strand repeats - Telomeric MetaboliteCHEBI:15986 (ChEBI)
G-strand Chromosome end with two additional single strand repeats and a subterminal loop - Telomeric R-HSA-182791 (Reactome)
G-strand chromosome end - TelomericMetaboliteCHEBI:15986 (ChEBI)
G-strand chromosome end - Telomeric MetaboliteCHEBI:15986 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFJ ProteinQ9BTM1 (Uniprot-TrEMBL)
H2AFV ProteinQ71UI9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
HIST3H3 ProteinQ16695 (Uniprot-TrEMBL)
LIG1ProteinP18858 (Uniprot-TrEMBL)
NHP2ProteinQ9NX24 (Uniprot-TrEMBL)
NTPComplexR-ALL-30595 (Reactome)
NucleosomeComplexR-HSA-181921 (Reactome) This is a generic nucleosome created for the telomerase module. It contains Histones H2A, H2B, and H3 as candidate sets where all of the variants of each histone protein are entered as candidates (as opposed to members). The list for each is not exhaustive, but rather is a list of histones known to Reactome at the time of the creation of the nucleosome complex. Histone H4 is only documented once in Uniprot, so for now it is an EWAS.
PCNA ProteinP12004 (Uniprot-TrEMBL)
PCNA homotrimerComplexR-HSA-68440 (Reactome)
POLA1 ProteinP09884 (Uniprot-TrEMBL)
POLA2 ProteinQ14181 (Uniprot-TrEMBL)
POLD1 ProteinP28340 (Uniprot-TrEMBL)
POLD2 ProteinP49005 (Uniprot-TrEMBL)
POLD3 ProteinQ15054 (Uniprot-TrEMBL)
POLD4 ProteinQ9HCU8 (Uniprot-TrEMBL)
POLE ProteinQ07864 (Uniprot-TrEMBL)
POLE2 ProteinP56282 (Uniprot-TrEMBL)
POLE3 ProteinQ9NRF9 (Uniprot-TrEMBL)
POLE4 ProteinQ9NR33 (Uniprot-TrEMBL)
POT1 ProteinQ9NUX5 (Uniprot-TrEMBL)
POT1ProteinQ9NUX5 (Uniprot-TrEMBL)
PRIM1 ProteinP49642 (Uniprot-TrEMBL)
PRIM2 ProteinP49643 (Uniprot-TrEMBL)
Processive complex

loaded on telomere:Okazaki

fragment complex
ComplexR-HSA-174435 (Reactome)
Processive complex

loaded on telomere:Okazaki fragment:Flap:RPA

heterotrimer:dna2
ComplexR-HSA-174442 (Reactome)
Processive complex

loaded on telomere:Okazaki fragment:Flap:RPA

heterotrimer
ComplexR-HSA-174436 (Reactome)
Processive complex

loaded on telomere:Okazaki

fragment:Flap
ComplexR-HSA-174431 (Reactome)
Processive complex

loaded on telomere:Okazaki fragments:Remaining

Flap
ComplexR-HSA-174440 (Reactome)
Processive complex

loaded on telomere:ligated C-strand Okazaki

fragments
ComplexR-HSA-176394 (Reactome)
Processive complex

loaded on telomere:nicked DNA from adjacent

Okazaki fragments
ComplexR-HSA-174432 (Reactome)
Processive complex loaded on telomereComplexR-HSA-174453 (Reactome)
RFC

Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA

homotrimer
ComplexR-HSA-174449 (Reactome)
RFC

Heteropentamer:RNA primer-DNA primer:G-strand extended telomere

end
ComplexR-HSA-174454 (Reactome)
RFC HeteropentamerComplexR-HSA-68436 (Reactome)
RFC1 ProteinP35251 (Uniprot-TrEMBL)
RFC2 ProteinP35250 (Uniprot-TrEMBL)
RFC3 ProteinP40938 (Uniprot-TrEMBL)
RFC4 ProteinP35249 (Uniprot-TrEMBL)
RFC5 ProteinP40937 (Uniprot-TrEMBL)
RNA primer R-ALL-68422 (Reactome)
RNA primer-DNA

primer:G-strand extended

telomere:PCNA
ComplexR-HSA-174450 (Reactome)
RNA primer-DNA

primer:G-strand

extended telomere
ComplexR-HSA-174433 (Reactome)
RNA primer:G-strand

extended telomere end:DNA polymerase alpha:primase

complex
ComplexR-HSA-174434 (Reactome)
RPA heterotrimerComplexR-HSA-68462 (Reactome)
RPA1 ProteinP27694 (Uniprot-TrEMBL)
RPA2 ProteinP15927 (Uniprot-TrEMBL)
RPA3 ProteinP35244 (Uniprot-TrEMBL)
RUVBL1ProteinQ9Y265 (Uniprot-TrEMBL)
RUVBL2ProteinQ9Y230 (Uniprot-TrEMBL)
Remaining Flap R-ALL-68467 (Reactome)
Shelterin complexComplexR-HSA-174898 (Reactome)
TERF1 ProteinP54274 (Uniprot-TrEMBL)
TERF2 ProteinQ15554 (Uniprot-TrEMBL)
TERF2IP ProteinQ9NYB0 (Uniprot-TrEMBL)
TERT ProteinO14746 (Uniprot-TrEMBL)
TERTProteinO14746 (Uniprot-TrEMBL)
TINF2 ProteinQ9BSI4 (Uniprot-TrEMBL)
Telomerase

Holoenzyme Base-paired to the Telomeric Chromosome End with an Additional single Stranded

Telomere repeat
ComplexR-HSA-164684 (Reactome)
Telomerase Holoenzyme:Telomeric RNP End with Two Additional Single Stranded Telomere RepeatsComplexR-HSA-164619 (Reactome)
Telomerase

RNP:Telomeric Chromosome End with an Additional single Stranded

Telomere repeat
ComplexR-HSA-163098 (Reactome)
Telomerase RNA Component (TERC)RnaU86046 (EMBL)
Telomerase RNA Component (TERC) ProteinU86046 (EMBL)
Telomerase RNP Bound

and base-paired to the Telomeric

Chromosome End
ComplexR-HSA-164683 (Reactome)
Telomerase RNP Bound

to the Telomeric

Chromosome End
ComplexR-HSA-163088 (Reactome)
Telomerase RNPComplexR-HSA-163101 (Reactome)
UTP MetaboliteCHEBI:15713 (ChEBI)
WRAP53ProteinQ9BUR4 (Uniprot-TrEMBL)
adenosine 5'-monophosphateMetaboliteCHEBI:16027 (ChEBI)
cytidine 5'-monophosphateMetaboliteCHEBI:17361 (ChEBI)
dATPMetaboliteCHEBI:16284 (ChEBI)
dCTPMetaboliteCHEBI:16311 (ChEBI)
dGTPMetaboliteCHEBI:16497 (ChEBI)
dTTPMetaboliteCHEBI:18077 (ChEBI)
guanosine 5'-monophosphateMetaboliteCHEBI:17345 (ChEBI)
ligated C-strand Okazaki fragment R-ALL-176395 (Reactome)
uridine 5'-monophosphateMetaboliteCHEBI:16695 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-174439 (Reactome)
ATPR-HSA-174439 (Reactome)
DKC1R-HSA-164616 (Reactome)
DNA Polymerase delta tetramerArrowR-HSA-176702 (Reactome)
DNA Polymerase delta tetramerR-HSA-174448 (Reactome)
DNA Polymerase delta tetramermim-catalysisR-HSA-174444 (Reactome)
DNA polymerase

alpha:primase:DNA polymerase alpha:G-strand extended telomere

end
R-HSA-174425 (Reactome)
DNA polymerase

alpha:primase:DNA polymerase alpha:G-strand extended telomere

end
mim-catalysisR-HSA-174425 (Reactome)
DNA polymerase alpha:primaseArrowR-HSA-174452 (Reactome)
DNA polymerase alpha:primasemim-catalysisR-HSA-174427 (Reactome)
DNA polymerase epsilonArrowR-HSA-174425 (Reactome)
DNA2ArrowR-HSA-174441 (Reactome)
DNA2R-HSA-174451 (Reactome)
Extended And

Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order

Structure
ArrowR-HSA-176700 (Reactome)
Extended And

Processed Telomere End and Associated DNA Binding and Packaging Protein

Complex
ArrowR-HSA-181450 (Reactome)
Extended And

Processed Telomere

End
ArrowR-HSA-176702 (Reactome)
Extended And

Processed Telomere

End
R-HSA-176700 (Reactome)
Extended And

Processed Telomere

End
R-HSA-181450 (Reactome)
FEN1mim-catalysisR-HSA-174446 (Reactome)
G-strand Chromosome

end with two additional single strand repeats -

Telomeric
ArrowR-HSA-163120 (Reactome)
G-strand chromosome end - TelomericR-HSA-163096 (Reactome)
LIG1mim-catalysisR-HSA-174456 (Reactome)
NHP2ArrowR-HSA-164616 (Reactome)
NTPR-HSA-174425 (Reactome)
NucleosomeR-HSA-176700 (Reactome)
NucleosomeR-HSA-181450 (Reactome)
PCNA homotrimerArrowR-HSA-176702 (Reactome)
PCNA homotrimerR-HSA-174439 (Reactome)
POT1R-HSA-176700 (Reactome)
POT1R-HSA-181450 (Reactome)
Processive complex

loaded on telomere:Okazaki

fragment complex
ArrowR-HSA-174444 (Reactome)
Processive complex

loaded on telomere:Okazaki

fragment complex
R-HSA-174438 (Reactome)
Processive complex

loaded on telomere:Okazaki fragment:Flap:RPA

heterotrimer:dna2
ArrowR-HSA-174451 (Reactome)
Processive complex

loaded on telomere:Okazaki fragment:Flap:RPA

heterotrimer:dna2
R-HSA-174441 (Reactome)
Processive complex

loaded on telomere:Okazaki fragment:Flap:RPA

heterotrimer
ArrowR-HSA-174445 (Reactome)
Processive complex

loaded on telomere:Okazaki fragment:Flap:RPA

heterotrimer
R-HSA-174451 (Reactome)
Processive complex

loaded on telomere:Okazaki

fragment:Flap
ArrowR-HSA-174438 (Reactome)
Processive complex

loaded on telomere:Okazaki

fragment:Flap
R-HSA-174445 (Reactome)
Processive complex

loaded on telomere:Okazaki fragments:Remaining

Flap
ArrowR-HSA-174441 (Reactome)
Processive complex

loaded on telomere:Okazaki fragments:Remaining

Flap
R-HSA-174446 (Reactome)
Processive complex

loaded on telomere:ligated C-strand Okazaki

fragments
ArrowR-HSA-174456 (Reactome)
Processive complex

loaded on telomere:ligated C-strand Okazaki

fragments
R-HSA-176702 (Reactome)
Processive complex

loaded on telomere:nicked DNA from adjacent

Okazaki fragments
ArrowR-HSA-174446 (Reactome)
Processive complex

loaded on telomere:nicked DNA from adjacent

Okazaki fragments
R-HSA-174456 (Reactome)
Processive complex loaded on telomereArrowR-HSA-174448 (Reactome)
Processive complex loaded on telomereR-HSA-174444 (Reactome)
R-HSA-163090 (Reactome) The template of hTERC directs the sequential addition of nucleotides to the 3' telomeric DNA end. Following addition of a nucleotide, the template and catalytic site must move relative to one another within the telomerase RNP to place the appropriate template residue in the active site. As base-pairing and nucleotide addition occur at one end of the template, base pair melting occurs at the other (Collins and Greider 1993; Wang and Blackburn, 1997; Hammond and Cech 1998; Benjamin et al. 2000; Forstemann and Lingner 2005). This un-pairing is thought to reduce the energy used for mediating the subsequent translocation step. Nucleotide addition can occur up until the template boundary which in hTERC is defined by a helix called P1b (Chen and Greider 2003).

R-HSA-163096 (Reactome) Studies in yeast and humans indicate that recruitment of telomerase to a telomere may be influenced by multiple variables, including regulatory protein factors, hTERT domains, telomere length, and the cell cycle. First, in yeast, the telomerase associated factor Est1 and the single-strand DNA binding protein Cdc13 play roles in telomerase recruitment (Pennock et al. 2001; Bianchi et al. 2004). Analogous proteins exist in human cells (Est1A, Est1B, Est1C, and POT1, respectively); however, how or whether these proteins are directly involved in telomerase recruitment remains to be elucidated. Second, N-terminal residues of hTERT within the DAT (dissociate the activities of telomerase) domain may have a role in binding single stranded telomeric DNA as the "anchor site" (Lee et al. 1993; Moriarty et al. 2005). Third, a cis-acting mechanism in yeast and humans that regulates telomere length maintenance may modulate telomerase access to the telomere (reviewed in Blackburn 2001; Smogorzewska and de Lange, 2004). Long telomeres, which have more associated protein factors, are in a state that is acted on by telomerase less frequently than that of short telomeres, which have fewer associated factors. Whether short telomeres actively recruit telomerase remains to be determined. Last, the recruitment of telomerase to telomeres shows cell-cycle regulation (Taggart et al. 2002; Smith et al. 2003; Fisher et al. 2004; Jady et al. 2006; Tomlinson et al. 2006). Further studies will be needed to determine the details of how human telomerase is recruited to a telomere.

R-HSA-163099 (Reactome) In vitro studies of telomerase complexes derived from multiple organisms indicate that at least two types of interactions are important for telomerase RNP catalytic site alignment at the 3' G-rich single-strand telomere end. In one interaction, an alignment region in hTERC base-pairs with the 3' G-rich single-strand telomeric DNA end to form an RNA-DNA hybrid, which positions the template adjacent to the 3' end of the telomere. In a second interaction, a portion of hTERT is proposed to interact with the DNA 5' of the telomerase RNA/DNA primer hybrid (Harrington and Greider 1991; Morin 1991; Moriarty et al. 2005), which is important for the catalytic rate (Lee and Blackburn, 1993) and presumably allows telomerase to maintain contact with the chromosome during the translocation step. How the anchor site binding and template hybridization are coordinated is not known.

R-HSA-163120 (Reactome) In vitro, telomerase can disassociate from the primer following addition of each nucleotide or during the translocation step. The regulation of telomerase disassociation from the telomere in vivo is not well-characterized. One factor that may be involved is a helicase termed hPIF1, which can unanneal the telomerase RNA/telomeric DNA hybrid (Boule et al., 2005; Zhang et al., 2006).

R-HSA-164616 (Reactome) hTERC is transcribed as a precursor and is processed at its 3' end to yield a 451 nucleotide RNA (Zaug et al. 1996). The accumulation of hTERC that has undergone this processing event requires a conserved region of sequence termed the box H/ACA motif (Mitchell et al. 1999a). This motif is bound by a complex containing dyskerin, and mutations in dyskerin affect the processing and accumulation of hTERC (Mitchell et al. 1999b; Mitchell and Collins 2000; Fu and Collins 2003). Recent studies of purified, catalytically active telomerase indicate that the minimal structure that has telomerase activity in vitro is a complex of one molecule of hTERC RNA and two each of hTERT and DKC1 (dyskerin) proteins (Cohen et al. 2007). Several additional proteins may associate with this minimal complex and modulate its activity. RUVBL1 (pontin), RUVBL2 (reptin), and TCAB1 (telomere Cajal body protein 1) are found associated with human telomerase RNPs purified from HeLa cells, and activities of these proteins are required for telomerase RNP assembly in vivo (Venteicher et al. 2008, 2009). NHP2 (NOLA2) is likewise associated with telomerase ribonucleoprotein complexes (Pogacic et al. 2000) and homozygosity for NHP2 mutations is associated with telomerase failure (dyskeratosis congenita) in humans (Vuillamy et al. 2008). The exact roles of the additional proteins in the assembly and function of telomerase RNP in vivo remain unclear, however, so they are annotated simply as positively regulating telomerase RNP formation.


The core components hTERC and hTERT undergo trafficking in the cell that may be important for telomerase function. hTERC has been found localized in multiple nuclear structures, including Cajal bodies, nucleoli, and at telomeres (Mitchell et al. 1999a; Jady et al. 2004; Zhu et al. 2004; Jady et al. 2006; Tomlinson et al. 2006). hTERT is also reported localize in Cajal bodies, nucleoli, and to associate with telomeres (Etheridge et al. 2002; Wong et al. 2002; Yang et al. 2002; Zhu et al. 2004; Tomlinson et al. 2006). Some of the factors that regulate trafficking of these two core components of telomerase have been identified, such as nucleolin (Khurts et al. 2004), SMN (Bachand et al. 2002), and 14-3-3 (Seimiya et al. 2000). Cytological studies of HeLa cells suggest that the localization of the telomerase core components can change through the cell-cycle (Jady et al. 2006; Tomlinson et al. 2006). Despite these studies, it is not clear in which compartment hTERT and hTERC assemble to form functional telomerase RNP.


The assembly of telomerase involves the chaperone proteins p23 and Hsp90, which stably associate with telomerase in vitro (Holt et al. 1999; Forsythe et al. 2001; Keppler et al. 2006). A number of other proteins interact with the telomerase RNP, but it is not clear if they play a role in telomerase assembly. Interestingly, assembled human telomerase RNP can multimerize, though the function of multimerization remains unclear (Beattie et al. 2001; Wenz et al. 2001; Arai et al. 2002).
R-HSA-164617 (Reactome) The elongation reaction proceeds as follows: The template of hTERC directs the sequential addition of nucleotides to the 3' telomeric DNA end. Following addition of a nucleotide, the template and catalytic site must move relative to one another within the telomerase RNP to place the appropriate template residue in the active site. As base-pairing and nucleotide addition occur at one end of the template, base pair melting occurs at the other (Collins and Greider 1993; Wang and Blackburn, 1997; Hammond and Cech 1998; Benjamin et al. 2000; Forstemann and Lingner 2005). This un-pairing is thought to reduce the energy used for mediating the subsequent translocation step. Nucleotide addition can occur up until the template boundary which in hTERC is defined by a helix called P1b (Chen and Greider 2003).

R-HSA-164620 (Reactome) The human telomerase RNP can catalyze multiple rounds of repeat addition on the same telomeric substrate in vitro. Before initiating synthesis of another repeat, telomerase undergoes a translocation step to reposition itself on the telomere. Base pairs in the DNA/RNA hybrid are unannealed, the RNA template is repositioned relative to the active site, and the template base-pairs at the 3' end of the newly synthesized DNA. The anchor site interaction with DNA 5' of the RNA-DNA duplex is thought to maintain the interaction of telomerase with DNA during the translocation step.

R-HSA-174425 (Reactome) The complementary strand is synthesized by the polymerase primase complex using conventional RNA priming.
R-HSA-174427 (Reactome) The complementary strand is synthesized by the polymerase primase complex using conventional RNA priming (Dai et al. 2010).
R-HSA-174438 (Reactome) When the polymerase delta:PCNA complex reaches a downstream Okazaki fragment, strand displacement synthesis occurs. The primer containing 5'-terminus of the downstream Okazaki fragment is folded into a single-stranded flap.
R-HSA-174439 (Reactome) The binding of the primer recognition complex involves the loading of proliferating cell nuclear antigen (PCNA). Replication Factor C transiently opens the PCNA toroid in an ATP-dependent reaction, and then allows PCNA to re-close around the double helix adjacent to the primer terminus. This leads to the formation of the "sliding clamp".
R-HSA-174441 (Reactome) The Dna2 endonuclease removes the initiator RNA along with several downstream deoxyribonucleotides. The cleavage of the single-stranded RNA substrate results in the disassembly of RPA and Dna2. The current data for the role of the Dna2 endonuclease has been derived from studies with yeast and Xenopus Dna2.
R-HSA-174444 (Reactome) After RFC initiates the assembly of the primer recognition complex, the complex of pol delta and PCNA is responsible for incorporating the additional nucleotides prior to the position of the next downstream initiator RNA primer. On the lagging strand, short discontinuous segments of DNA, called Okazaki fragments, are synthesized on RNA primers. The average length of the Okazaki fragments is 100 nucleotides. Polymerase switching is a key event that allows the processive synthesis of DNA by the pol delta and PCNA complex.
R-HSA-174445 (Reactome) The first step in the removal of the flap intermediate is the binding of Replication Protein A (RPA) to the long flap structure. RPA is a eukaryotic single-stranded DNA binding protein.
R-HSA-174446 (Reactome) The remaining flap, which is too short to support RPA binding, is then processed by FEN-1. There is evidence that binding of RPA to the displaced end of the RNA-containing Okazaki fragment prevents FEN-1 from accessing the substrate. FEN-1 is a structure-specific endonuclease that cleaves near the base of the flap at a position one nucleotide into the annealed region. Biochemical studies have shown that the preferred substrate for FEN-1 consists of a one-nucleotide 3'-tail on the upstream primer in addition to the 5'-flap of the downstream primer.
R-HSA-174447 (Reactome) Replication factor C is proposed to dissociate from PCNA following sliding clamp formation, and the DNA toroid alone tethers pol delta to the DNA.
R-HSA-174448 (Reactome) The loading of proliferating cell nuclear antigen (PCNA) leads to recruitment of pol delta, the process of polymerase switching. Human PCNA is a homotrimer of 36 kDa subunits that form a toroidal structure. The loading of PCNA by RFC is a key event in the transition from the priming mode to the extension mode of DNA synthesis. The processive complex is composed of the pol delta holoenzyme and PCNA (Murakami et al.2010).
R-HSA-174451 (Reactome) After RPA binds the long flap, it recruits the Dna2 endonuclease. Dna2 endonuclease removes most of the flap, but the job of complete removal of the flap is then completed by FEN-1.
R-HSA-174452 (Reactome) Once the RNA-DNA primer is synthesized, replication factor C (RFC) initiates a reaction called "polymerase switching"; pol delta, the processive enzyme replaces pol alpha, the priming enzyme. RFC binds to the 3'-end of the RNA-DNA primer on the Primosome, to displace the pol alpha primase complex. The binding of RFC triggers the binding of the primer recognition complex.
R-HSA-174456 (Reactome) Removal of the flap by FEN-1 leads to the generation of a nick between the 3'-end of the upstream Okazaki fragment and the 5'-end of the downstream Okazaki fragment. DNA ligase I then seals the nicks between adjacent processed Okazaki fragments to generate intact double-stranded DNA at the telomere.
R-HSA-176700 (Reactome) In addition to telomerase-mediated elongation and C-strand synthesis, other DNA processing steps are likely involved in telomere maintenance. In humans, nucleolytic activity is proposed to be involved in generating the G-rich 3' single strand overhang. In addition, differences in the structure of the overhang at telomeres that have undergone leading vs. lagging strand replication suggest that DNA processing may be different at these telomeres (Chai et al. 2006).


Electron microscopy studies of purified human telomeric DNA have provided evidence for telomeric loops, or t-loops (Griffith et al. 1999). t-loops are proposed to result from invasion of the 3' G-rich single strand overhang into the double stranded portion of the telomeric TTAGGG repeat tract. The strand displaced by invasion forms a structure called a D loop. The function of the t-loop is presumed to be the protection of the 3' telomeric end. In vitro, the double strand telomeric DNA binding protein TRF2 can increase the frequency of t-loop formation. The prevalence of the t-loops in vivo is not known.
Many proteins associate with telomeric DNA. One complex that binds telomeres is called shelterin. Shelterin is a six-protein complex composed of TRF1 and TRF2, which can bind double-stranded telomeric DNA, POT1, which can bind single-stranded telomeric DNA, and three other factors, RAP1, TIN2, and TPP1 (reviewed in de Lange 2006 "Telomeres"). Human telomeric DNA is also bound by nucleosomes (Makarov et al. 1993; Nikitina and Woodcock 2004). A number of other proteins, including some that play roles in the DNA damage response, can be found at telomeres (Zhu et al. 2000; Verdun et al. 2005).
Studies in yeast and humans indicate that the association of many proteins with telomeres is regulated through the cell cycle (Smith et al. 1993; Zhu et al. 2000; Taggart et al. 2002; Fisher et al. 2004; Takata et al. 2004; Takata et al. 2005; Verdun et al. 2005). For instance, TRF1, MRE11, POT1, ATM, and NBS1 display cell cycle regulated chromatin immunoprecipitation of telomeric DNA (Zhu et al. 2000; Verdun et al. 2005), and cytologically observable hTERT and hTERC localize to a subset of telomeres only in S-phase (Jady et al. 2006; Tomlinson et al. 2006). These data indicate that telomeres are dynamically remodeled through the cell cycle.


R-HSA-176702 (Reactome) At some point in the extension process a sufficient number of regulatory factors that repress telomere extension become bound to the extending telomere. These factors include the TRF1 complexes, TRF2 complexes, telomerase, other factors, and the telomere itself. As repeats are added to the G-rich strand, and once lagging strand synthesis completes the duplex, new binding sites become available for these repressive factors. Once a balance is reached between telomere extension and the telomere repression factors, extension ceases. In this state extension machinery disassociates, leaving the telomere to be folded into a stable conformation.

This module details a single transit through the telomere extension process, detailing the addition of two repeats, and the corresponding synthesis of a section of lagging strand. An actual round of in vivo telomere extension would require thousands of telomere repeat additions, and it is the repressive effect of the factors bound to these repeats that turns off telomere extension (Moldovan et al. 2007).

R-HSA-181450 (Reactome) In addition to telomerase-mediated elongation and C-strand synthesis, other DNA processing steps are likely involved in telomere maintenance. In humans, nucleolytic activity is proposed to be involved in generating the G-rich 3' single strand overhang. In addition, differences in the structure of the overhang at telomeres that have undergone leading vs. lagging strand replication suggest that DNA processing may be different at these telomeres (Chai et al. 2006).

Many proteins associate with telomeric DNA. One complex that binds telomeres is called shelterin. Shelterin is a six-protein complex composed of TRF1 and TRF2, which can bind double-stranded telomeric DNA, POT1, which can bind single-stranded telomeric DNA, and three other factors, RAP1, TIN2, and TPP1 (reviewed in de Lange 2006 "Telomeres"). Human telomeric DNA is also bound by nucleosomes (Makarov et al. 1993; Nikitina and Woodcock 2004). A number of other proteins, including some that play roles in the DNA damage response, can be found at telomeres (Zhu et al. 2000; Verdun et al. 2005).

Studies in yeast and humans indicate that the association of many proteins with telomeres is regulated through the cell cycle (Zhu et al. 2000; Taggart et al. 2002; Fisher et al. 2004; Takata et al. 2004; Takata et al. 2005; Verdun et al. 2005). For instance, TRF1, MRE11, POT1, ATM, and NBS1 display cell cycle regulated chromatin immunoprecipitation of telomeric DNA (Zhu et al. 2000; Verdun et al. 2005), and cytologically observable hTERT and hTERC localize to a subset of telomeres only in S-phase (Jady et al. 2006; Tomlinson et al. 2006). These data indicate that telomeres are dynamically remodeled through the cell cycle.

RFC

Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA

homotrimer
ArrowR-HSA-174439 (Reactome)
RFC

Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA

homotrimer
R-HSA-174447 (Reactome)
RFC

Heteropentamer:RNA primer-DNA primer:G-strand extended telomere

end
ArrowR-HSA-174452 (Reactome)
RFC

Heteropentamer:RNA primer-DNA primer:G-strand extended telomere

end
R-HSA-174439 (Reactome)
RFC HeteropentamerArrowR-HSA-174447 (Reactome)
RFC HeteropentamerR-HSA-174452 (Reactome)
RNA primer-DNA

primer:G-strand extended

telomere:PCNA
ArrowR-HSA-174447 (Reactome)
RNA primer-DNA

primer:G-strand extended

telomere:PCNA
R-HSA-174448 (Reactome)
RNA primer-DNA

primer:G-strand

extended telomere
ArrowR-HSA-174427 (Reactome)
RNA primer-DNA

primer:G-strand

extended telomere
R-HSA-174452 (Reactome)
RNA primer:G-strand

extended telomere end:DNA polymerase alpha:primase

complex
ArrowR-HSA-174425 (Reactome)
RNA primer:G-strand

extended telomere end:DNA polymerase alpha:primase

complex
R-HSA-174427 (Reactome)
RPA heterotrimerArrowR-HSA-174441 (Reactome)
RPA heterotrimerR-HSA-174445 (Reactome)
RUVBL1ArrowR-HSA-164616 (Reactome)
RUVBL2ArrowR-HSA-164616 (Reactome)
Shelterin complexR-HSA-176700 (Reactome)
Shelterin complexR-HSA-181450 (Reactome)
TERTR-HSA-164616 (Reactome)
Telomerase

Holoenzyme Base-paired to the Telomeric Chromosome End with an Additional single Stranded

Telomere repeat
ArrowR-HSA-164620 (Reactome)
Telomerase Holoenzyme:Telomeric RNP End with Two Additional Single Stranded Telomere RepeatsArrowR-HSA-164617 (Reactome)
Telomerase Holoenzyme:Telomeric RNP End with Two Additional Single Stranded Telomere RepeatsR-HSA-163120 (Reactome)
Telomerase

RNP:Telomeric Chromosome End with an Additional single Stranded

Telomere repeat
ArrowR-HSA-163090 (Reactome)
Telomerase

RNP:Telomeric Chromosome End with an Additional single Stranded

Telomere repeat
R-HSA-164617 (Reactome)
Telomerase

RNP:Telomeric Chromosome End with an Additional single Stranded

Telomere repeat
R-HSA-164620 (Reactome)
Telomerase RNA Component (TERC)R-HSA-164616 (Reactome)
Telomerase RNP Bound

and base-paired to the Telomeric

Chromosome End
ArrowR-HSA-163099 (Reactome)
Telomerase RNP Bound

and base-paired to the Telomeric

Chromosome End
R-HSA-163090 (Reactome)
Telomerase RNP Bound

to the Telomeric

Chromosome End
ArrowR-HSA-163096 (Reactome)
Telomerase RNP Bound

to the Telomeric

Chromosome End
R-HSA-163099 (Reactome)
Telomerase RNPArrowR-HSA-163120 (Reactome)
Telomerase RNPArrowR-HSA-164616 (Reactome)
Telomerase RNPR-HSA-163096 (Reactome)
Telomerase RNPmim-catalysisR-HSA-163090 (Reactome)
Telomerase RNPmim-catalysisR-HSA-164617 (Reactome)
WRAP53ArrowR-HSA-164616 (Reactome)
adenosine 5'-monophosphateArrowR-HSA-174441 (Reactome)
cytidine 5'-monophosphateArrowR-HSA-174441 (Reactome)
dATPR-HSA-163090 (Reactome)
dATPR-HSA-164617 (Reactome)
dATPR-HSA-174427 (Reactome)
dATPR-HSA-174444 (Reactome)
dCTPR-HSA-163090 (Reactome)
dCTPR-HSA-164617 (Reactome)
dCTPR-HSA-174427 (Reactome)
dCTPR-HSA-174444 (Reactome)
dGTPR-HSA-163090 (Reactome)
dGTPR-HSA-164617 (Reactome)
dGTPR-HSA-174427 (Reactome)
dGTPR-HSA-174444 (Reactome)
dTTPR-HSA-163090 (Reactome)
dTTPR-HSA-164617 (Reactome)
dTTPR-HSA-174427 (Reactome)
dTTPR-HSA-174444 (Reactome)
guanosine 5'-monophosphateArrowR-HSA-174441 (Reactome)
uridine 5'-monophosphateArrowR-HSA-174441 (Reactome)
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