1: Mol Biol (Mosk). 2006 Jul-Aug;40(4):580-94.


[Telomerase: structure and properties of the enzyme, characteristics of the yeast telomerase]

[Article in Russian]

Shcherbakova DM, Zvereva ME, Shpanchenko OV, Dontsova OA.

Telomerase is a ribonucleoprotein that extends the telomeric ends of the chromosomes to counterbalance the natural shortening due to incomplete DNA replication in eukaryotic cells. The core enzyme consists of catalytic reverse transcriptase subunit TERT (Telomerase Reverse Transcriptase) and RNA subunit TER (Telomerase RNA), a short specific region of which serves as a template for synthesis of the telomeric repeats. In this review we focus on the telomerase from yeast Saccharomyces cerevisiae. Despite the intensive research of telomerase in different organisms, the enzyme mechanism remains unclear. The observed peculiarities of the yeast telomerase is of great interest too. Unlike ciliate and human telomerases, yeast enzyme can add only one telomeric repeat to a DNA oligonucleotide (primer) imitating the single-stranded telomeric end of the chromosome and remains stably bound to it after elongation. This review is an attempt to summarise results of numerous studies of the structure and functions of the core enzyme components, their interactions between each other and with a primer, telomerase activity on different substrates in vitro. Also the peculiarities of the telomerase functioning in a cell and accessory proteins of the telomerase complex are discussed.

Publication Types:
English Abstract
Research Support, Non-U.S. Gov't
Review

PMID: 16913218 [PubMed - indexed for MEDLINE]

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2: Annu Rev Biochem. 2006;75:493-517.


The structure and function of telomerase reverse transcriptase.

Autexier C, Lue NF.

Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Quebec, Canada. chantal.autexier@mcgill.ca

The structure and integrity of telomeres are essential for genome stability. Telomere dysregulation can lead to cell death, cell senescence, or abnormal cell proliferation. The maintenance of telomere repeats in most eukaryotic organisms requires telomerase, which consists of a reverse transcriptase (RT) and an RNA template that dictates the synthesis of the G-rich strand of telomere terminal repeats. Structurally, telomerase reverse transcriptase (TERT) contains unique and variable N- and C-terminal extensions that flank a central RT-like domain. The enzymology of telomerase includes features that are both similar to and distinct from those characteristic of other RTs. Two distinguishing features of TERT are its stable association with the telomerase RNA and its ability to repetitively reverse transcribe the template segment of RNA. Here we discuss TERT structure and function; its regulation by RNA-DNA, TERT-DNA, TERT-RNA, TERT-TERT interactions, and TERT-associated proteins; and the relationship between telomerase enzymology and telomere maintenance.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

PMID: 16756500 [PubMed - indexed for MEDLINE]

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3: Curr Opin Struct Biol. 2006 Jun;16(3):307-18. Epub 2006 May 18.


Structure and function of telomerase RNA.

Theimer CA, Feigon J.

Department of Chemistry and Biochemistry, and Molecular Biology Institute, University of California, Los Angeles, CA 90095-1569, USA.

Maintenance of telomeres by the enzyme telomerase is essential for genomic stability and cell viability in ciliates, vertebrates and yeast. The minimal components of telomerase required for catalytic activity are the telomerase reverse transcriptase (TERT) protein and the template-containing telomerase RNA (TER). Recent studies have afforded significant advances in the biophysical characterization of telomerase RNAs from various species. The first TER structures have been reported, for regions of the catalytically essential pseudoknot and CR4/CR5 domains of human TER, and provide a structural basis for interpretation of mutational and biochemical data. The domains and interactions of the Tetrahymena thermophila telomerase holoenzyme RNA and protein components have been further characterized biochemically, and structures of the TER template boundary element and the N-terminal domain of T. thermophila TERT have been determined. Phylogenetic and biochemical analyses of yeast TERs have revealed core structural elements in common with ciliates and vertebrates, and the minimal domains required for function in vivo.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Review

PMID: 16713250 [PubMed - indexed for MEDLINE]

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4: Nippon Rinsho. 2004 Jul;62(7):1277-82.


[Telomerase inhibitor, telomestatin, a specific mechanism to interact with telomere structure]

[Article in Japanese]

Shin-ya K.

Institute of Molecular and Cellular Biosciences, The University of Tokyo.

A novel telomerase inhibitor, telomestatin, isolated from Streptomyces anulatus is the most potent telomerase inhibitor so far. Telomestatin specifically inhibited telomerase without affecting reverse transcriptases and polymerases. In addition, telomestatin induced telomere shortening, but its ratio was extremely faster than that observed in physiological telomere shortening. These results suggested the existence of other mechanisms to inhibit telomerase. Telomeres consist of guanine rich sequences which compose a characteristic three-dimensional structure designated as G-quadruplex. Stabilization of G-quadruplex structure inhibited the catalysis of not only telomerase but also other DNA interacting molecules. Telomestatin potently stabilized G-quadruplex structure in a specific manner. G-quadruplex structure is also involved in a lot of oncogene promoters. Thus, telomestatin provide the novel therapeutic molecular target for cancer chemotherapy.

Publication Types:
English Abstract
Review

PMID: 15283144 [PubMed - indexed for MEDLINE]

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5: Trends Biochem Sci. 2004 Apr;29(4):183-92.


Telomerase RNA structure and function: implications for dyskeratosis congenita.

Chen JL, Greider CW.

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 15082312 [PubMed - indexed for MEDLINE]

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6: Mini Rev Med Chem. 2001 May;1(1):31-41.


DNA tetraplex-binding drugs: structure-selective targeting is critical for antitumour telomerase inhibition.

Perry PJ, Jenkins TC.

Yorkshire Cancer Research Laboratory of Drug Design, University of Bradford, West Yorkshire BD7 1DP, UK.

Four-stranded tetraplex ("G-quadruplex") DNA represents a new paradigm for the design of DNA-interactive antitumour drugs, as the formed DNA-drug complexes have been suggested to interfere with critical telomerase function. The unique structural features presented by tetraplex over duplex DNA have stimulated the design of small ligand molecules able to selectively promote the formation and/or stabilisation of such higher-order DNA structures. Current developments in tetraplex-targeted telomerase inhibitors, and importantly their DNA structural selectivity, are explored.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 12369989 [PubMed - indexed for MEDLINE]

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7: Pharmacol Ther. 2000 Mar;85(3):133-9.


Structure-activity relationships among guanine-quadruplex telomerase inhibitors.

Neidle S, Harrison RJ, Reszka AP, Read MA.

CRC Biomolecular Structure Unit, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London, UK. s.neidle@icr.ac.uk

The ribonucleoprotein telomerase is responsible for maintaining the length of telomeric ends of chromosomes in tumour cells. It is activated in over 85% of the tumour cells, and is emerging as a major target for cancer chemotherapy. A range of molecules containing tricyclic and tetracyclic aromatic chromophores has been shown to inhibit the telomerase enzyme system at the micromolar level. There is evidence that they do so via stabilisation of a guanine-quadruplex structure, which provides a stop signal for further telomere elongation. The known structure-activity relationships for these compounds are summarised, and pointers for the development of future molecules with enhanced selectivity are described.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10739868 [PubMed - indexed for MEDLINE]

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8: Nippon Rinsho. 1998 May;56(5):1102-7.


[Structure and regulation mechanisms of telomerase]

[Article in Japanese]

Nakayama J, Ishikawa F.

Department of Life Science, Tokyo Institute of Technology.

Telomerase is a specialized type of reverse transcriptase which catalyzes the synthesis of telomeric DNA using intrinsic RNA as a template. The enzyme was originally found in a ciliate Tetrahymena, and has been extensively investigated using ciliates or budding yeast. In mammals, the enzyme is highly active in most cancer cells and germ cells, but is inactive in most somatic cells, suggesting the activation of telomerase may be important for the continued cell growth or progression of cancer cells. Recently, two protein components of the mammalian telomerase have been identified using homology to the sequencing data from unicellular eukaryotes. Interestingly, telomerase activity was induced by the expression of catalytic subunit, hTERT, in telomerase-negative normal fibroblast cells, indicating that it plays a key role in the activation of telomerase in cancer cells.

Publication Types:
English Abstract
Review

PMID: 9613104 [PubMed - indexed for MEDLINE]

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9: Eur J Cancer. 1997 Apr;33(5):792-800.


Telomere structure and telomerase expression during mouse development and tumorigenesis.

Kipling D.

Department of Pathology, University of Wales College of Medicine, Cardiff, U.K.

Mouse telomeres are on average longer than those of man, raising questions regarding the link between telomere loss and replicative senescence in mice and the requirement for telomerase activity for mouse cell immortalisation. However, the emerging data on telomerase activity during tumorigenesis in the mouse must be interpreted in the context of the very different structure of mouse telomeres. It will be argued here that the evidence for a casual link between telomere loss and replicative senescence is weak in the mouse, with the observed upregulation of telomerase activity in mouse tumours perhaps instead reflecting co-ordinated regulatory changes in tumour cells. Its absence would be consistent with evolutionary considerations, which hypothesise that such a link is an additional layer of control against tumour formation that has evolved in man. The very different genomic substrates for telomerase in humans and mice mean that the initial phenotype of a telomerase knock-out mouse does not necessarily critically address the existence of a link between telomerase and tumorigenesis in man.

Publication Types:
Review

PMID: 9282119 [PubMed - indexed for MEDLINE]

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10: Curr Opin Cell Biol. 1996 Jun;8(3):374-80.


Structure and function of telomerase.

Collins K.

Department of Molecular and Cell Biology, University of California, Berkeley 94720-3204, USA. collins@mendel.berkeley.edu

The study of eukaryotic telomeres at the molecular level began with the discovery of short, tandem repeats at Tetrahymena chromosome ends. In the following two decades, major insights about telomere structure and function have come from investigations of telomerase, the DNA polymerase that synthesizes these repeats. In the past year, three areas of telomerase research have been particularly intense: assays of telomerase activity, isolation of telomerase components, and studies of the regulation of telomerase and telomere length in vivo.

Publication Types:
Review

PMID: 8743890 [PubMed - indexed for MEDLINE]