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Telomere length regulation: coupling DNA end processing to feedback regulation of telomerase.

Shore D, Bianchi A - EMBO J. (2009)

Bottom Line: The prevailing notion in the field is that telomere length regulation is brought about through a negative feedback mechanism that 'counts' TG repeat-bound protein complexes to generate a signal that regulates telomerase action.This review summarizes experiments leading up to this model and then focuses on more recent experiments, primarily from yeast, that begin to suggest how this 'counting' mechanism might work.The emerging picture is that of a complex interplay between the conventional DNA replication machinery, DNA damage response factors, and a specialized set of proteins that help to recruit and regulate the telomerase enzyme.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and NCCR Program 'Frontiers in Genetics', University of Geneva, Sciences III, Geneva, Switzerland. David.Shore@molbio.unige.ch

ABSTRACT
The conventional DNA polymerase machinery is unable to fully replicate the ends of linear chromosomes. To surmount this problem, nearly all eukaryotes use the telomerase enzyme, a specialized reverse transcriptase that utilizes its own RNA template to add short TG-rich repeats to chromosome ends, thus reversing their gradual erosion occurring at each round of replication. This unique, non-DNA templated mode of telomere replication requires a regulatory mechanism to ensure that telomerase acts at telomeres whose TG tracts are too short, but not at those with long tracts, thus maintaining the protective TG repeat 'cap' at an appropriate average length. The prevailing notion in the field is that telomere length regulation is brought about through a negative feedback mechanism that 'counts' TG repeat-bound protein complexes to generate a signal that regulates telomerase action. This review summarizes experiments leading up to this model and then focuses on more recent experiments, primarily from yeast, that begin to suggest how this 'counting' mechanism might work. The emerging picture is that of a complex interplay between the conventional DNA replication machinery, DNA damage response factors, and a specialized set of proteins that help to recruit and regulate the telomerase enzyme.

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Related in: MedlinePlus

Possible mechanisms of telomerase regulation by the shelterin complex in mammalian cells. The formation of a t-loop by the shelterin complex (not indicated here) is thought to sequester the telomere 3′ terminus from telomerase. Opening of the t-loop will generate a structure (left) that may still provide only limited access to telomerase, perhaps due to the TPP1–TIN2 interaction. In this case, a transition to a more open structure (right) might be required to allow efficient recruitment of telomerase by POT1–TPP1. See main text for more details and a description of related events thought to occur at telomeres in the fission yeast S. pombe.
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f4: Possible mechanisms of telomerase regulation by the shelterin complex in mammalian cells. The formation of a t-loop by the shelterin complex (not indicated here) is thought to sequester the telomere 3′ terminus from telomerase. Opening of the t-loop will generate a structure (left) that may still provide only limited access to telomerase, perhaps due to the TPP1–TIN2 interaction. In this case, a transition to a more open structure (right) might be required to allow efficient recruitment of telomerase by POT1–TPP1. See main text for more details and a description of related events thought to occur at telomeres in the fission yeast S. pombe.

Mentions: In mammals, telomeric duplex DNA is bound by two Myb domain protein homodimers, TRF1 and TRF2. In these systems, the Rap1 orthologue is recruited by a direct interaction with TRF2, whereas a novel protein, TIN2, interacts with both TRF1 and TRF2 and provides the key bridge to the TPP1–POT1 telomere end-binding complex. Together, this complex of six proteins is referred to as the ‘shelterin' complex, to denote its key role in both telomere protection and telomerase-based telomere maintenance (de Lange, 2005). It is unclear whether a telomere-length dependent switch in telomerase regulation similar to the one postulated above for fission yeast also operates in mammals, but this is of course a possibility given the similarities between the telomeric complexes in the two systems. Indeed, a mechanism to relay information regarding repeat-array length to the overhang that is the substrate for telomerase has been proposed in human cells, based on the dual ability of POT1 to indirectly interact with double-stranded repeat binding factors and also to directly bind the single-stranded overhang (Loayza and De Lange, 2003; Wang et al, 2007; Xin et al, 2007; see Figure 4). Consistent with these ideas, TPP1 interacts with telomerase and has been proposed to recruit the enzyme to chromosome ends (Xin et al, 2007). Again, the details of how this process might be regulated are still unknown, and the involvement of additional proteins is likely, perhaps including human Est1.


Telomere length regulation: coupling DNA end processing to feedback regulation of telomerase.

Shore D, Bianchi A - EMBO J. (2009)

Possible mechanisms of telomerase regulation by the shelterin complex in mammalian cells. The formation of a t-loop by the shelterin complex (not indicated here) is thought to sequester the telomere 3′ terminus from telomerase. Opening of the t-loop will generate a structure (left) that may still provide only limited access to telomerase, perhaps due to the TPP1–TIN2 interaction. In this case, a transition to a more open structure (right) might be required to allow efficient recruitment of telomerase by POT1–TPP1. See main text for more details and a description of related events thought to occur at telomeres in the fission yeast S. pombe.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2722252&req=5

f4: Possible mechanisms of telomerase regulation by the shelterin complex in mammalian cells. The formation of a t-loop by the shelterin complex (not indicated here) is thought to sequester the telomere 3′ terminus from telomerase. Opening of the t-loop will generate a structure (left) that may still provide only limited access to telomerase, perhaps due to the TPP1–TIN2 interaction. In this case, a transition to a more open structure (right) might be required to allow efficient recruitment of telomerase by POT1–TPP1. See main text for more details and a description of related events thought to occur at telomeres in the fission yeast S. pombe.
Mentions: In mammals, telomeric duplex DNA is bound by two Myb domain protein homodimers, TRF1 and TRF2. In these systems, the Rap1 orthologue is recruited by a direct interaction with TRF2, whereas a novel protein, TIN2, interacts with both TRF1 and TRF2 and provides the key bridge to the TPP1–POT1 telomere end-binding complex. Together, this complex of six proteins is referred to as the ‘shelterin' complex, to denote its key role in both telomere protection and telomerase-based telomere maintenance (de Lange, 2005). It is unclear whether a telomere-length dependent switch in telomerase regulation similar to the one postulated above for fission yeast also operates in mammals, but this is of course a possibility given the similarities between the telomeric complexes in the two systems. Indeed, a mechanism to relay information regarding repeat-array length to the overhang that is the substrate for telomerase has been proposed in human cells, based on the dual ability of POT1 to indirectly interact with double-stranded repeat binding factors and also to directly bind the single-stranded overhang (Loayza and De Lange, 2003; Wang et al, 2007; Xin et al, 2007; see Figure 4). Consistent with these ideas, TPP1 interacts with telomerase and has been proposed to recruit the enzyme to chromosome ends (Xin et al, 2007). Again, the details of how this process might be regulated are still unknown, and the involvement of additional proteins is likely, perhaps including human Est1.

Bottom Line: The prevailing notion in the field is that telomere length regulation is brought about through a negative feedback mechanism that 'counts' TG repeat-bound protein complexes to generate a signal that regulates telomerase action.This review summarizes experiments leading up to this model and then focuses on more recent experiments, primarily from yeast, that begin to suggest how this 'counting' mechanism might work.The emerging picture is that of a complex interplay between the conventional DNA replication machinery, DNA damage response factors, and a specialized set of proteins that help to recruit and regulate the telomerase enzyme.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and NCCR Program 'Frontiers in Genetics', University of Geneva, Sciences III, Geneva, Switzerland. David.Shore@molbio.unige.ch

ABSTRACT
The conventional DNA polymerase machinery is unable to fully replicate the ends of linear chromosomes. To surmount this problem, nearly all eukaryotes use the telomerase enzyme, a specialized reverse transcriptase that utilizes its own RNA template to add short TG-rich repeats to chromosome ends, thus reversing their gradual erosion occurring at each round of replication. This unique, non-DNA templated mode of telomere replication requires a regulatory mechanism to ensure that telomerase acts at telomeres whose TG tracts are too short, but not at those with long tracts, thus maintaining the protective TG repeat 'cap' at an appropriate average length. The prevailing notion in the field is that telomere length regulation is brought about through a negative feedback mechanism that 'counts' TG repeat-bound protein complexes to generate a signal that regulates telomerase action. This review summarizes experiments leading up to this model and then focuses on more recent experiments, primarily from yeast, that begin to suggest how this 'counting' mechanism might work. The emerging picture is that of a complex interplay between the conventional DNA replication machinery, DNA damage response factors, and a specialized set of proteins that help to recruit and regulate the telomerase enzyme.

Show MeSH
Related in: MedlinePlus