Telomere Maintenance (Homo sapiens)

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1, 6, 7, 9-12, 1762, 3, 5, 15, 16, 18...116146466nucleoplasmRFC4 POLD4 POLD2 dTTPPRIM1 DNA2 PCNA G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric ADPPOLD1 POT1 FEN1Telomerase RNAComponent (TERC) POLD2 POT1 POLD4 ACD POLD1 POLA1 G-strand chromosomeend - Telomeric PCNA UMPPRIM2 PCNA HIST1H4 POLD3 G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric RFC3 ACD RPA2 DNA polymerasealpha:primaseExtended AndProcessed TelomereEnd and AssociatedDNA Binding andPackaging ProteinComplexDKC1 POLE2 GMPTINF2 POLD3 Processive complexloaded ontelomere:Okazakifragments:RemainingFlapPOLA2 RFC2 TERF2IP TelomeraseHoloenzymeBase-paired to theTelomericChromosome End withan Additionalsingle StrandedTelomere repeatPOLA1 RFC2 POLD2 RFCHeteropentamer:RNAprimer-DNAprimer:G-strandextended telomereend duplex:PCNAhomotrimerHIST3H3 POT1TINF2 RPA3 HIST1H4 RFC HeteropentamerProcessive complexloaded ontelomere:Okazakifragment complexTERF1 RUVBL2AMPG-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric POLD3 TERF2 Telomerase RNPTERTPOLD4 NTPWRAP53RNA primer:G-strandextended telomereend:DNA polymerasealpha:primasecomplexPOLD3 POLE POLA2 PCNA POLD2 RFC4 POLD3 Shelterin complexRPA3 DKC1 POLD1 POLD1 TERF1 RPA1 POLD4 RFC1 TERT PCNA homotrimerTelomeraseHoloenzyme:Telomeric RNP End with Two Additional Single Stranded Telomere RepeatsTelomerase RNAComponent (TERC) G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric LIG1:APEX1RPA1 Telomerase RNAComponent (TERC) PCNA POLD3 POLD1 POLD2 DKC1 DKC1 PRIM2 Telomerase RNAComponent (TERC) RPA2 RFC3 TERF2 POLD2 POLD4 POLD2 RNA primer-DNAprimer:G-strandextendedtelomere:PCNARFC5 PCNA RFC1 POLD1 PRIM2 POLD4 RFC5 RPA1 POLD4 Extended AndProcessed TelomereEnd and AssociatedDNA Binding andPackaging ProteinComplex Folded IntoHigher OrderStructureRNA primer-DNAprimer:G-strandextended telomereG-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric Processive complexloaded ontelomere:Okazakifragment:Flap:RPAheterotrimer:dna2NucleosomePRIM1 G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric POLD1 POLE RFC3 TINF2 dATPDKC1 PCNA POLD4 RFC1 HIST3H3 Processive complexloaded ontelomere:Okazakifragment:FlapPOLD4 TERT DNA2G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric DNA polymeraseepsilonRFC2 POLD3 POLD3 Telomerase RNAComponent (TERC)Processive complexloaded ontelomere:nicked DNAfrom adjacentOkazaki fragmentsG-strand chromosomeend - TelomericTERF2 NHP2POLA2 TERF1 RPA3 Telomerase RNAComponent (TERC) PCNA POLE2 TERT dGTPLIG1 Extended AndProcessed TelomereEndPOLA1 TERT POLA2 POLD1 G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric Telomerase RNAComponent (TERC) dCTPHIST1H4 G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric Telomerase RNP Boundand base-paired tothe TelomericChromosome EndDKC1 RFC5 G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric RUVBL1PCNA G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric POLD2 ACD Telomerase RNP Boundto the TelomericChromosome EndPCNA RPA heterotrimerTERT TelomeraseRNP:TelomericChromosome End withan Additionalsingle StrandedTelomere repeatCMPG-strand Chromosomeend with twoadditional singlestrand repeats -TelomericG-strand Chromosomeend with anadditional singlestrand repeat -Telomeric PRIM1 POLD1 G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric TERT POT1 POLA1 HIST3H3 PCNA Processive complexloaded ontelomere:ligatedC-strand OkazakifragmentsG-strand Chromosomeend with anadditional singlestrand repeat -Telomeric G-strand chromosomeend - Telomeric G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric ATPPRIM1 Processive complexloaded on telomereDNA Polymerase deltatetramerRFCHeteropentamer:RNAprimer-DNAprimer:G-strandextended telomereendProcessive complexloaded ontelomere:Okazakifragment:Flap:RPAheterotrimerTERF2IP RFC4 APEX1 POLD2 G-strand Chromosomeend with twoadditional singlestrand repeats -Telomeric DNA polymerasealpha:primase:DNApolymerasealpha:G-strandextended telomereendTERF2IP RPA2 POLD3 PRIM2 DKC12813


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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Bibliography

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History

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CompareRevisionActionTimeUserComment
114708view16:18, 25 January 2021ReactomeTeamReactome version 75
113153view11:21, 2 November 2020ReactomeTeamReactome version 74
112381view15:31, 9 October 2020ReactomeTeamReactome version 73
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)
AMPMetaboliteCHEBI:16027 (ChEBI)
APEX1 ProteinP27695 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CMPMetaboliteCHEBI:17361 (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)
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)
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 -

Telomeric		CHEBI:15986 (ChEBI)
G-strand chromosome end - Telomeric MetaboliteCHEBI:15986 (ChEBI)
G-strand chromosome end - TelomericCHEBI:15986 (ChEBI)
GMPMetaboliteCHEBI:17345 (ChEBI)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST3H3 ProteinQ16695 (Uniprot-TrEMBL)
LIG1 ProteinP18858 (Uniprot-TrEMBL)
LIG1:APEX1ComplexR-HSA-110348 (Reactome)
NHP2ProteinQ9NX24 (Uniprot-TrEMBL)
NTPR-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)
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-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)
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) ProteinU86046 (EMBL)
Telomerase RNA Component (TERC)RnaU86046 (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)
UMPMetaboliteCHEBI:16695 (ChEBI)
WRAP53ProteinQ9BUR4 (Uniprot-TrEMBL)
dATPMetaboliteCHEBI:16284 (ChEBI)
dCTPMetaboliteCHEBI:16311 (ChEBI)
dGTPMetaboliteCHEBI:16497 (ChEBI)
dTTPMetaboliteCHEBI:18077 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-174439 (Reactome)
AMPArrowR-HSA-174441 (Reactome)
ATPR-HSA-174439 (Reactome)
CMPArrowR-HSA-174441 (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:primaseArrowR-HSA-174452 (Reactome)
DNA polymerase alpha:primasemim-catalysisR-HSA-174425 (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)
GMPArrowR-HSA-174441 (Reactome)
LIG1:APEX1mim-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.
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. 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.
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.

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)
UMPArrowR-HSA-174441 (Reactome)
WRAP53ArrowR-HSA-164616 (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)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1928"
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