Wang, F. et al. The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature 445, 506-510

Department of Biological Chemistry, University of Michigan Medical School, MSRBIII 5301D, 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
Nature (Impact Factor: 41.46). 03/2007; 445(7127):506-10. DOI: 10.1038/nature05454
Source: PubMed


Telomeres were originally defined as chromosome caps that prevent the natural ends of linear chromosomes from undergoing deleterious degradation and fusion events. POT1 (protection of telomeres) protein binds the single-stranded G-rich DNA overhangs at human chromosome ends and suppresses unwanted DNA repair activities. TPP1 is a previously identified binding partner of POT1 that has been proposed to form part of a six-protein shelterin complex at telomeres. Here, the crystal structure of a domain of human TPP1 reveals an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan, suggesting that TPP1 is the missing beta-subunit of human POT1 protein. Telomeric DNA end-binding proteins have generally been found to inhibit rather than stimulate the action of the chromosome end-replicating enzyme, telomerase. In contrast, we find that TPP1 and POT1 form a complex with telomeric DNA that increases the activity and processivity of the human telomerase core enzyme. We propose that POT1-TPP1 switches from inhibiting telomerase access to the telomere, as a component of shelterin, to serving as a processivity factor for telomerase during telomere extension.

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    • "TRF2 represses ataxia-telangiectasia mutated (ATM)-mediated DDR and non-homologous end joining, while POT1 inhibits DNA-damage kinase ataxia-telangiectasia and Rad3 related (ATR) (Denchi and de Lange, 2007; Karlseder et al., 2004). Contrastingly, the POT1-TPP1 complex positively regulates TL, likely due to the role of TPP1 in the recruitment of telomerase (Nandakumar et al., 2012; Wang et al., 2007). While a clear role of RAP1 has not been established, it has been shown to be involved in homologous recombination and inhibition of the DDR, and is recruited to telomeres via TRF2 (Sfeir et al., 2010). "
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    ABSTRACT: Telomeres are the heterochromatic repeat regions at the ends of eukaryotic chromosomes, whose length is considered to be a determinant of biological ageing. Normal ageing itself is associated with telomere shortening. Here, critically short telomeres trigger senescence and eventually cell death. This shortening rate may be further increased by inflammation and oxidative stress and thus affect the ageing process. Apart from shortened or dysfunctional telomeres, cells undergoing senescence are also associated with hyperactivity of the transcription factor NF-κB and overexpression of inflammatory cytokines such as TNF-α, IL-6, and IFN-γ in circulating macrophages. Interestingly, telomerase, a reverse transcriptase that elongates telomeres, is involved in modulating NF-κB activity. Furthermore, inflammation and oxidative stress are implicated as pre-disease mechanisms for chronic diseases of ageing such as neurodegenerative diseases, cardiovascular disease, and cancer. To date, inflammation and telomere shortening have mostly been studied individually in terms of ageing and the associated disease phenotype. However, the interdependent nature of the two demands a more synergistic approach in understanding the ageing process itself and for developing new therapeutic approaches. In this review, we aim to summarize the intricate association between the various inflammatory molecules and telomeres that together contribute to the ageing process and related diseases.
    No preview · Article · Nov 2015 · Ageing Research Reviews
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    • "In vitro, the POT1–TPP1 complex substantially increases the RAP of telomerase while only having a small impact on activity (Wang et al. 2007). POT1–TPP1 is proposed to decrease the dissociation rate of telomerase from its telomeric substrate and aid the translocation step (Fig. 3; Latrick and Cech 2010). "
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    ABSTRACT: Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species. © 2015 Schmidt and Cech Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Jun 2015 · Genes & development
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    • "However, despite the evolutionary tuning of telomerase to synthesize multiple repeats processively, translocation is an inefficient step and primers frequently dissociate [49]. A number of studies indicate that TPP1 is a processivity factor for human telomerase during active telomeric synthesis [2] [41] [42] [52]. TPP1 mediates its role as a processivity factor at least in part by reducing the telomerase–substrate off-rate [42]. "
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    ABSTRACT: Telomere maintenance is a highly coordinated process, and its misregulation is linked to cancer as well as telomere-shortening syndromes. Recent studies have shown that the TEL-patch - a cluster of amino acids on the surface of the shelterin component TPP1 - is necessary for the recruitment of telomerase to the telomere in human cells. However, there has been only basic biochemical analysis of the role of TPP1 in the telomerase recruitment process. Here we develop an in vitro assay to quantitatively measure the contribution of the TEL-patch to telomerase recruitment - binding and extension of the first telomeric repeat. We also demonstrate that the TEL-patch contributes to the translocation step of the telomerase reaction. Finally, our quantitative observations indicate that the TEL-patch stabilizes the association between telomerase and telomeric DNA substrates, providing a molecular explanation for its contributions to telomerase recruitment and action. Copyright © 2015. Published by Elsevier Ltd.
    Preview · Article · Jan 2015 · Journal of Molecular Biology
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