Telomere Maintenance (Homo sapiens)
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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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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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DataNodes
alpha:primase:DNA polymerase alpha:G-strand extended telomere
endProcessed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order
StructureProcessed Telomere End and Associated DNA Binding and Packaging Protein
ComplexProcessed Telomere
Endend with two additional single strand repeats -
Telomericloaded on telomere:Okazaki
fragment complexloaded on telomere:Okazaki fragment:Flap:RPA
heterotrimer:dna2loaded on telomere:Okazaki fragment:Flap:RPA
heterotrimerloaded on telomere:Okazaki
fragment:Flaploaded on telomere:Okazaki fragments:Remaining
Flaploaded on telomere:ligated C-strand Okazaki
fragmentsloaded on telomere:nicked DNA from adjacent
Okazaki fragmentsHeteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA
homotrimerHeteropentamer:RNA primer-DNA primer:G-strand extended telomere
endprimer:G-strand extended
telomere:PCNAprimer:G-strand
extended telomereextended telomere end:DNA polymerase alpha:primase
complexHoloenzyme Base-paired to the Telomeric Chromosome End with an Additional single Stranded
Telomere repeatRNP:Telomeric Chromosome End with an Additional single Stranded
Telomere repeatand base-paired to the Telomeric
Chromosome Endto the Telomeric
Chromosome EndAnnotated Interactions
alpha:primase:DNA polymerase alpha:G-strand extended telomere
endProcessed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order
StructureProcessed Telomere End and Associated DNA Binding and Packaging Protein
ComplexProcessed Telomere
EndProcessed Telomere
EndProcessed Telomere
Endend with two additional single strand repeats -
Telomericloaded on telomere:Okazaki
fragment complexloaded on telomere:Okazaki
fragment complexloaded on telomere:Okazaki fragment:Flap:RPA
heterotrimer:dna2loaded on telomere:Okazaki fragment:Flap:RPA
heterotrimer:dna2loaded on telomere:Okazaki fragment:Flap:RPA
heterotrimerloaded on telomere:Okazaki fragment:Flap:RPA
heterotrimerloaded on telomere:Okazaki
fragment:Flaploaded on telomere:Okazaki
fragment:Flaploaded on telomere:Okazaki fragments:Remaining
Flaploaded on telomere:Okazaki fragments:Remaining
Flaploaded on telomere:ligated C-strand Okazaki
fragmentsloaded on telomere:ligated C-strand Okazaki
fragmentsloaded on telomere:nicked DNA from adjacent
Okazaki fragmentsloaded on telomere:nicked DNA from adjacent
Okazaki fragmentsThe 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).
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.
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.
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.
Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA
homotrimerHeteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA
homotrimerHeteropentamer:RNA primer-DNA primer:G-strand extended telomere
endHeteropentamer:RNA primer-DNA primer:G-strand extended telomere
endprimer:G-strand extended
telomere:PCNAprimer:G-strand extended
telomere:PCNAprimer:G-strand
extended telomereprimer:G-strand
extended telomereextended telomere end:DNA polymerase alpha:primase
complexextended telomere end:DNA polymerase alpha:primase
complexHoloenzyme Base-paired to the Telomeric Chromosome End with an Additional single Stranded
Telomere repeatRNP:Telomeric Chromosome End with an Additional single Stranded
Telomere repeatRNP:Telomeric Chromosome End with an Additional single Stranded
Telomere repeatRNP:Telomeric Chromosome End with an Additional single Stranded
Telomere repeatand base-paired to the Telomeric
Chromosome Endand base-paired to the Telomeric
Chromosome Endto the Telomeric
Chromosome Endto the Telomeric
Chromosome End