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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    • "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.
    Genes & development 06/2015; 29(11):1095-1105. DOI:10.1101/gad.263863.115 · 10.80 Impact Factor
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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.
    Journal of Molecular Biology 01/2015; 427(6). DOI:10.1016/j.jmb.2015.01.008 · 4.33 Impact Factor
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    • "Tpp1 cannot bind to telomere sequence directly, but binds to the Pot1-ssDNA complex and enhances the Pot1-ssDNA interaction. It is identified as a binding partner of Pot1, and Tpp1-Pot1 association enhances Pot1 affinity for telomeric single strand DNA (Baumann and Cech, 2001; Wang et al., 2007; Xin et al., 2007). The binding of the Pot1-Tpp1 complex to telomeric ssDNA serves to cap telomere ends and prevent telomerase access to ssDNA template. "
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    ABSTRACT: Telomere plays key roles in maintaining chromosome stability and cell replicative capacity. Telomere shortening occur concomitant with aging. Abnormal short telomere associated with some diseases, such as dyskeratosis congenita, idiopathic pulmonary fibrosis and aplastic anemia. Telomere is longer in pluripotent stem cells than in somatic cells. During preimplantation development, the telomeres lengthen significantly. Furthermore, during somatic cell reprogramming, telomere elongation is of great importance in the acquisition of authentic pluripotency. This review focuses primarily on regulatory mechanisms of telomere length, telomere length maintenance in pluripotent cells, telomere length extension in early embryo development, and also on telomere rejuvenation in somatic cell reprogramming. Telomere related diseases were also touched in this review. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 10/2014; 229(10). DOI:10.1002/jcp.24537 · 3.84 Impact Factor
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