Telomere Maintenance (Homo sapiens)
From WikiPathways
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.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=157579
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.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=157579
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History
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External references
DataNodes
| View all... |
| Name | Type | Database reference | Comment |
|---|---|---|---|
| ACD [nucleoplasm] | Protein | Q96AP0 (Uniprot-TrEMBL)  | |
| ADP | Metabolite | CHEBI:16761 (ChEBI) | |
| AMP | Metabolite | CHEBI:16027 (ChEBI) | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| CMP | Metabolite | CHEBI:17361 (ChEBI) | |
| DKC1 [nucleoplasm] | Protein | O60832 (Uniprot-TrEMBL) | |
| DKC1 | Protein | O60832 (Uniprot-TrEMBL) | |
| DNA Polymerase delta tetramer | Complex | REACT_5801 (Reactome) | |
| DNA polymerase
alpha:primase:DNA polymerase alpha:G-strand extended telomere end | Complex | REACT_8177 (Reactome) | |
| DNA polymerase alpha:primase | Complex | REACT_3725 (Reactome) | |
| DNA polymerase epsilon | Complex | REACT_4621 (Reactome) | |
| DNA2 [nucleoplasm] | Protein | P51530 (Uniprot-TrEMBL) | |
| DNA2 | Protein | P51530 (Uniprot-TrEMBL) | |
| Extended And
Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order Structure | Complex | REACT_8525 (Reactome) | |
| Extended And
Processed Telomere End and Associated DNA Binding and Packaging Protein Complex | Complex | REACT_8626 (Reactome) | |
| Extended And
Processed Telomere End | Complex | REACT_8288 (Reactome) | |
| FEN1 | Protein | P39748 (Uniprot-TrEMBL) | |
| G-strand Chromosome
end with an additional single strand repeat - Telomeric [nucleoplasm] | Metabolite | CHEBI:15986 (ChEBI) | |
| G-strand Chromosome
end with two additional single strand repeats - Telomeric [nucleoplasm] | Metabolite | CHEBI:15986 (ChEBI) | |
| G-strand Chromosome
end with two additional single strand repeats - Telomeric | CHEBI:15986 (ChEBI) | ||
| G-strand chromosome
end - Telomeric [nucleoplasm] | Metabolite | CHEBI:15986 (ChEBI) | |
| G-strand chromosome end - Telomeric | CHEBI:15986 (ChEBI) | ||
| GMP | Metabolite | CHEBI:17345 (ChEBI) | |
| HIST1H4A [nucleoplasm] | Protein | P62805 (Uniprot-TrEMBL) | |
| HIST3H3 [nucleoplasm] | Protein | Q16695 (Uniprot-TrEMBL) | |
| LIG1 | Protein | P18858 (Uniprot-TrEMBL) | |
| NHP2 | Protein | Q9NX24 (Uniprot-TrEMBL) | |
| NTP | Metabolite | REACT_4491 (Reactome) | |
| Nucleosome | Complex | REACT_8671 (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 [nucleoplasm] | Protein | P12004 (Uniprot-TrEMBL) | |
| PCNA homotrimer | Complex | REACT_2542 (Reactome) | |
| POLA1 [nucleoplasm] | Protein | P09884 (Uniprot-TrEMBL) | |
| POLA2 [nucleoplasm] | Protein | Q14181 (Uniprot-TrEMBL) | |
| POLD1 [nucleoplasm] | Protein | P28340 (Uniprot-TrEMBL) | |
| POLD2 [nucleoplasm] | Protein | P49005 (Uniprot-TrEMBL) | |
| POLD3 [nucleoplasm] | Protein | Q15054 (Uniprot-TrEMBL) | |
| POLD4 [nucleoplasm] | Protein | Q9HCU8 (Uniprot-TrEMBL) | |
| POLE [nucleoplasm] | Protein | Q07864 (Uniprot-TrEMBL) | |
| POLE2 [nucleoplasm] | Protein | P56282 (Uniprot-TrEMBL) | |
| POT1 [nucleoplasm] | Protein | Q9NUX5 (Uniprot-TrEMBL) | |
| POT1 | Protein | Q9NUX5 (Uniprot-TrEMBL) | |
| PRIM1 [nucleoplasm] | Protein | P49642 (Uniprot-TrEMBL) | |
| PRIM2 [nucleoplasm] | Protein | P49643 (Uniprot-TrEMBL) | |
| Processive complex
loaded on telomere:Okazaki fragment complex | Complex | REACT_8837 (Reactome) | |
| Processive complex
loaded on telomere:Okazaki fragment:Flap:RPA heterotrimer:dna2 | Complex | REACT_8321 (Reactome) | |
| Processive complex
loaded on telomere:Okazaki fragment:Flap:RPA heterotrimer | Complex | REACT_8468 (Reactome) | |
| Processive complex
loaded on telomere:Okazaki fragment:Flap | Complex | REACT_8956 (Reactome) | |
| Processive complex
loaded on telomere:Okazaki fragments:Remaining Flap | Complex | REACT_8363 (Reactome) | |
| Processive complex
loaded on telomere:ligated C-strand Okazaki fragments | Complex | REACT_8541 (Reactome) | |
| Processive complex
loaded on telomere:nicked DNA from adjacent Okazaki fragments | Complex | REACT_8309 (Reactome) | |
| Processive complex loaded on telomere | Complex | REACT_8041 (Reactome) | |
| RFC
Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA homotrimer | Complex | REACT_8208 (Reactome) | |
| RFC
Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end | Complex | REACT_8972 (Reactome) | |
| RFC Heteropentamer | Complex | REACT_4881 (Reactome) | |
| RFC1 [nucleoplasm] | Protein | P35251 (Uniprot-TrEMBL) | |
| RFC2 [nucleoplasm] | Protein | P35250 (Uniprot-TrEMBL) | |
| RFC3 [nucleoplasm] | Protein | P40938 (Uniprot-TrEMBL) | |
| RFC4 [nucleoplasm] | Protein | P35249 (Uniprot-TrEMBL) | |
| RFC5 [nucleoplasm] | Protein | P40937 (Uniprot-TrEMBL) | |
| RNA primer-DNA
primer:G-strand extended telomere:PCNA | Complex | REACT_8843 (Reactome) | |
| RNA primer-DNA
primer:G-strand extended telomere | Complex | REACT_8560 (Reactome) | |
| RNA primer:G-strand
extended telomere end:DNA polymerase alpha:primase complex | Complex | REACT_8504 (Reactome) | |
| RPA heterotrimer | Complex | REACT_3427 (Reactome) | |
| RPA1 [nucleoplasm] | Protein | P27694 (Uniprot-TrEMBL) | |
| RPA2 [nucleoplasm] | Protein | P15927 (Uniprot-TrEMBL) | |
| RPA3 [nucleoplasm] | Protein | P35244 (Uniprot-TrEMBL) | |
| RUVBL1 | Protein | Q9Y265 (Uniprot-TrEMBL) | |
| RUVBL2 | Protein | Q9Y230 (Uniprot-TrEMBL) | |
| Shelterin complex | Complex | REACT_8593 (Reactome) | |
| TERF1 [nucleoplasm] | Protein | P54274 (Uniprot-TrEMBL) | |
| TERF2 [nucleoplasm] | Protein | Q15554 (Uniprot-TrEMBL) | |
| TERF2IP(2-399) [nucleoplasm] | Protein | Q9NYB0 (Uniprot-TrEMBL) | |
| TERT [nucleoplasm] | Protein | O14746 (Uniprot-TrEMBL) | |
| TERT | Protein | O14746 (Uniprot-TrEMBL) | |
| TINF2 [nucleoplasm] | Protein | Q9BSI4 (Uniprot-TrEMBL) | |
| Telomerase
Holoenzyme Base-paired to the Telomeric Chromosome End with an Additional single Stranded Telomere repeat | Complex | REACT_8180 (Reactome) | |
| Telomerase
Holoenzyme:Telomeric RNP End with Two Additional Single Stranded Telomere Repeats | Complex | REACT_8055 (Reactome) | |
| Telomerase
RNP:Telomeric Chromosome End with an Additional single Stranded Telomere repeat | Complex | REACT_8663 (Reactome) | |
| Telomerase RNA
Component (TERC) [nucleoplasm] | Protein | U86046 (EMBL) | |
| Telomerase RNA Component (TERC) | Rna | U86046 (EMBL) | |
| Telomerase RNP Bound
and base-paired to the Telomeric Chromosome End | Complex | REACT_8909 (Reactome) | |
| Telomerase RNP Bound
to the Telomeric Chromosome End | Complex | REACT_8788 (Reactome) | |
| Telomerase RNP | Complex | REACT_8548 (Reactome) | |
| UMP | Metabolite | CHEBI:16695 (ChEBI) | |
| WRAP53 | Protein | Q9BUR4 (Uniprot-TrEMBL) | |
| dATP | Metabolite | CHEBI:16284 (ChEBI) | |
| dCTP | Metabolite | CHEBI:16311 (ChEBI) | |
| dGTP | Metabolite | CHEBI:16497 (ChEBI) | |
| dTTP | Metabolite | CHEBI:18077 (ChEBI) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP | Arrow | REACT_8000 (Reactome) | ||
| AMP | Arrow | REACT_7955 (Reactome) | ||
| ATP | REACT_8000 (Reactome) | |||
| CMP | Arrow | REACT_7955 (Reactome) | ||
| DKC1 | REACT_7997 (Reactome) | |||
| DNA Polymerase delta tetramer | Arrow | REACT_7954 (Reactome) | ||
| DNA Polymerase delta tetramer | REACT_7979 (Reactome) | |||
| DNA Polymerase delta tetramer | mim-catalysis | REACT_8029 (Reactome) | ||
| DNA polymerase
alpha:primase:DNA polymerase alpha:G-strand extended telomere end | REACT_7998 (Reactome) | |||
| DNA polymerase alpha:primase | Arrow | REACT_8008 (Reactome) | ||
| DNA polymerase alpha:primase | mim-catalysis | REACT_7998 (Reactome) | ||
| DNA polymerase alpha:primase | mim-catalysis | REACT_8004 (Reactome) | ||
| DNA polymerase epsilon | Arrow | REACT_7998 (Reactome) | ||
| DNA2 | Arrow | REACT_7955 (Reactome) | ||
| DNA2 | REACT_8015 (Reactome) | |||
| Extended And
Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order Structure | Arrow | REACT_8031 (Reactome) | ||
| Extended And
Processed Telomere End and Associated DNA Binding and Packaging Protein Complex | Arrow | REACT_7971 (Reactome) | ||
| Extended And
Processed Telomere End | Arrow | REACT_7954 (Reactome) | ||
| Extended And
Processed Telomere End | REACT_7971 (Reactome) | |||
| Extended And
Processed Telomere End | REACT_8031 (Reactome) | |||
| FEN1 | mim-catalysis | REACT_7975 (Reactome) | ||
| G-strand Chromosome
end with two additional single strand repeats - Telomeric | Arrow | REACT_7996 (Reactome) | ||
| G-strand chromosome end - Telomeric | REACT_7960 (Reactome) | |||
| GMP | Arrow | REACT_7955 (Reactome) | ||
| LIG1 | mim-catalysis | REACT_7994 (Reactome) | ||
| NHP2 | Arrow | REACT_7997 (Reactome) | ||
| NTP | REACT_7998 (Reactome) | |||
| Nucleosome | REACT_7971 (Reactome) | |||
| Nucleosome | REACT_8031 (Reactome) | |||
| PCNA homotrimer | Arrow | REACT_7954 (Reactome) | ||
| PCNA homotrimer | REACT_8000 (Reactome) | |||
| POT1 | REACT_7971 (Reactome) | |||
| POT1 | REACT_8031 (Reactome) | |||
| Processive complex
loaded on telomere:Okazaki fragment complex | Arrow | REACT_8029 (Reactome) | ||
| Processive complex
loaded on telomere:Okazaki fragment complex | REACT_7973 (Reactome) | |||
| Processive complex
loaded on telomere:Okazaki fragment:Flap:RPA heterotrimer:dna2 | Arrow | REACT_8015 (Reactome) | ||
| Processive complex
loaded on telomere:Okazaki fragment:Flap:RPA heterotrimer:dna2 | REACT_7955 (Reactome) | |||
| Processive complex
loaded on telomere:Okazaki fragment:Flap:RPA heterotrimer | Arrow | REACT_7949 (Reactome) | ||
| Processive complex
loaded on telomere:Okazaki fragment:Flap:RPA heterotrimer | REACT_8015 (Reactome) | |||
| Processive complex
loaded on telomere:Okazaki fragment:Flap | Arrow | REACT_7973 (Reactome) | ||
| Processive complex
loaded on telomere:Okazaki fragment:Flap | REACT_7949 (Reactome) | |||
| Processive complex
loaded on telomere:Okazaki fragments:Remaining Flap | Arrow | REACT_7955 (Reactome) | ||
| Processive complex
loaded on telomere:Okazaki fragments:Remaining Flap | REACT_7975 (Reactome) | |||
| Processive complex
loaded on telomere:ligated C-strand Okazaki fragments | Arrow | REACT_7994 (Reactome) | ||
| Processive complex
loaded on telomere:ligated C-strand Okazaki fragments | REACT_7954 (Reactome) | |||
| Processive complex
loaded on telomere:nicked DNA from adjacent Okazaki fragments | Arrow | REACT_7975 (Reactome) | ||
| Processive complex
loaded on telomere:nicked DNA from adjacent Okazaki fragments | REACT_7994 (Reactome) | |||
| Processive complex loaded on telomere | Arrow | REACT_7979 (Reactome) | ||
| Processive complex loaded on telomere | REACT_8029 (Reactome) | |||
| REACT_7949 (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. | |||
| REACT_7954 (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. | |||
| REACT_7955 (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. | |||
| REACT_7957 (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. | |||
| REACT_7960 (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. | |||
| REACT_7967 (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. | |||
| REACT_7968 (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. | |||
| REACT_7971 (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. | |||
| REACT_7973 (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. | |||
| REACT_7975 (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. | |||
| REACT_7979 (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. | |||
| REACT_7985 (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). | |||
| REACT_7994 (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. | |||
| REACT_7996 (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). | |||
| REACT_7997 (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). | |||
| REACT_7998 (Reactome) | The complementary strand is synthesized by the polymerase primase complex using conventional RNA priming. | |||
| REACT_8000 (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". | |||
| REACT_8004 (Reactome) | The complementary strand is synthesized by the polymerase primase complex using conventional RNA priming. | |||
| REACT_8008 (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. | |||
| REACT_8015 (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. | |||
| REACT_8019 (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). | |||
| REACT_8029 (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. | |||
| REACT_8031 (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).
| |||
| RFC
Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA homotrimer | Arrow | REACT_8000 (Reactome) | ||
| RFC
Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA homotrimer | REACT_7967 (Reactome) | |||
| RFC
Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end | Arrow | REACT_8008 (Reactome) | ||
| RFC
Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end | REACT_8000 (Reactome) | |||
| RFC Heteropentamer | Arrow | REACT_7967 (Reactome) | ||
| RFC Heteropentamer | REACT_8008 (Reactome) | |||
| RNA primer-DNA
primer:G-strand extended telomere:PCNA | Arrow | REACT_7967 (Reactome) | ||
| RNA primer-DNA
primer:G-strand extended telomere:PCNA | REACT_7979 (Reactome) | |||
| RNA primer-DNA
primer:G-strand extended telomere | Arrow | REACT_8004 (Reactome) | ||
| RNA primer-DNA
primer:G-strand extended telomere | REACT_8008 (Reactome) | |||
| RNA primer:G-strand
extended telomere end:DNA polymerase alpha:primase complex | Arrow | REACT_7998 (Reactome) | ||
| RNA primer:G-strand
extended telomere end:DNA polymerase alpha:primase complex | REACT_8004 (Reactome) | |||
| RPA heterotrimer | Arrow | REACT_7955 (Reactome) | ||
| RPA heterotrimer | REACT_7949 (Reactome) | |||
| RUVBL1 | Arrow | REACT_7997 (Reactome) | ||
| RUVBL2 | Arrow | REACT_7997 (Reactome) | ||
| Shelterin complex | REACT_7971 (Reactome) | |||
| Shelterin complex | REACT_8031 (Reactome) | |||
| TERT | REACT_7997 (Reactome) | |||
| Telomerase
Holoenzyme Base-paired to the Telomeric Chromosome End with an Additional single Stranded Telomere repeat | Arrow | REACT_7957 (Reactome) | ||
| Telomerase
Holoenzyme:Telomeric RNP End with Two Additional Single Stranded Telomere Repeats | Arrow | REACT_7985 (Reactome) | ||
| Telomerase
Holoenzyme:Telomeric RNP End with Two Additional Single Stranded Telomere Repeats | REACT_7996 (Reactome) | |||
| Telomerase
RNP:Telomeric Chromosome End with an Additional single Stranded Telomere repeat | Arrow | REACT_8019 (Reactome) | ||
| Telomerase
RNP:Telomeric Chromosome End with an Additional single Stranded Telomere repeat | REACT_7957 (Reactome) | |||
| Telomerase
RNP:Telomeric Chromosome End with an Additional single Stranded Telomere repeat | REACT_7985 (Reactome) | |||
| Telomerase RNA Component (TERC) | REACT_7997 (Reactome) | |||
| Telomerase RNP Bound
and base-paired to the Telomeric Chromosome End | Arrow | REACT_7968 (Reactome) | ||
| Telomerase RNP Bound
and base-paired to the Telomeric Chromosome End | REACT_8019 (Reactome) | |||
| Telomerase RNP Bound
to the Telomeric Chromosome End | Arrow | REACT_7960 (Reactome) | ||
| Telomerase RNP Bound
to the Telomeric Chromosome End | REACT_7968 (Reactome) | |||
| Telomerase RNP | Arrow | REACT_7996 (Reactome) | ||
| Telomerase RNP | Arrow | REACT_7997 (Reactome) | ||
| Telomerase RNP | REACT_7960 (Reactome) | |||
| Telomerase RNP | mim-catalysis | REACT_7985 (Reactome) | ||
| Telomerase RNP | mim-catalysis | REACT_8019 (Reactome) | ||
| UMP | Arrow | REACT_7955 (Reactome) | ||
| WRAP53 | Arrow | REACT_7997 (Reactome) | ||
| dATP | REACT_7985 (Reactome) | |||
| dATP | REACT_8004 (Reactome) | |||
| dATP | REACT_8019 (Reactome) | |||
| dATP | REACT_8029 (Reactome) | |||
| dCTP | REACT_7985 (Reactome) | |||
| dCTP | REACT_8004 (Reactome) | |||
| dCTP | REACT_8019 (Reactome) | |||
| dCTP | REACT_8029 (Reactome) | |||
| dGTP | REACT_7985 (Reactome) | |||
| dGTP | REACT_8004 (Reactome) | |||
| dGTP | REACT_8019 (Reactome) | |||
| dGTP | REACT_8029 (Reactome) | |||
| dTTP | REACT_7985 (Reactome) | |||
| dTTP | REACT_8004 (Reactome) | |||
| dTTP | REACT_8019 (Reactome) | |||
| dTTP | REACT_8029 (Reactome) |
