Telomerase Function
Published by Anonymous on 2007/9/30 (5669 reads)
1: 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]
--------------------------------------------------------------------------------
2: 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]
--------------------------------------------------------------------------------
3: Crit Rev Oncol Hematol. 2005 May;54(2):85-93.
Telomerase: regulation, function and transformation.
Dong CK, Masutomi K, Hahn WC.
Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Work from several laboratories over the past decade indicates that the acquisition of constitutive telomerase expression is a critical step during the malignant transformation of human cells. Normal human cells transiently express low levels of telomerase, the ribonucleoprotein responsible for extending and maintaining telomeres, and exhibit telomere shortening after extended passage, whereas most cancers exhibit constitutive telomerase expression and maintain telomeres at stable lengths. These observations establish a direct connection between immortalization and stabilization of telomere structure. However, recent work suggests that telomerase also contributes to cancer development beyond its role in maintaining stable telomere lengths. In this review, we summarize recent observations that support the concept that telomerase plays multiple roles in facilitating human cell transformation.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15843091 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Sheng Li Ke Xue Jin Zhan. 2004 Apr;35(2):149-51.
[Recent advance of studies on telomerase function in stem cells]
[Article in Chinese]
Li J, Xie C, Pei XT.
Publication Types:
Review
PMID: 15285423 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
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]
--------------------------------------------------------------------------------
6: Cancer Lett. 2003 May 15;194(2):139-54.
Biochemical aspects of telomerase function.
Harrington L.
Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, 620 University Avenue, Rm. 932, Ontario M5G 2C1, Toronto, Canada. leah@uhnres.utoronto.ca <leah@uhnres.utoronto.ca>
Arthur Kornberg "never met a dull enzyme" (For the Love of Enzymes: The Odyssey of a Biochemist, Harvard University Press, 1989) and telomerase is no exception. Telomerase is a remarkable polymerase that uses an internal RNA template to reverse-transcribe telomere DNA, one nucleotide at a time, onto telomeric, G-rich single-stranded DNA. In the 17 years since its discovery, the characterization of telomerase enzyme components has uncovered a highly conserved family of telomerase reverse transcriptases that, together with the telomerase RNA, appear to comprise the enzymatic core of telomerase. While not as comprehensively understood as yet, some telomerase-associated proteins also serve crucial roles in telomerase function in vivo, such as telomerase ribonudeoprotein (RNP) assembly, recruitment to the telomere, and the coordination of DNA replication at the telomere. A selected overview of the biochemical properties of this unique enzyme, in vitro and in vivo, will be presented.
Publication Types:
Review
PMID: 12757972 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Tanpakushitsu Kakusan Koso. 2003 Mar;48(4 Suppl):501-7.
[Function of telomerase and heritable disease]
[Article in Japanese]
Nabetani A, Ishikawa F.
anabe@lif.kyoto-u.ac.jp
Publication Types:
Review
PMID: 12696160 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Pathol Oncol Res. 2001;7(3):161-70.
Telomerase: biological function and potential role in cancer management.
Chatziantoniou VD.
Semmelweis University, Budapest, Hungary. vchatzis@hotmail.com
Telomeres are the specialized ends of eukaryotic chromosomes, thought to have many functions, most importantly serving as a clock signaling entry into cellular senescence. These structures are maintained by the reverse transcriptase telomerase, a peculiar enzyme in both structure, since it contains its own template RNA and function, since it is inactivated in most normal tissues but activated in the vast majority of malignant tumors. These features have made telomerase a subject of intense investigation, both to understand its cellular role and regulation and to exploit its activation in cancer to develop drugs or diagnostic methods based on telomerase. This work gathers all the information currently available in the biological and clinical fields of telomerase research.
Publication Types:
Review
PMID: 11692141 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Gene. 2001 May 16;269(1-2):1-12.
Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT).
Poole JC, Andrews LG, Tollefsbol TO.
Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294-1170, USA.
Recent interest in the regulation of telomerase, the enzyme that maintains chromosomal termini, has lead to the discovery and characterization of the catalytic subunit of telomerase, hTERT. Many studies have suggested that the transcription of hTERT represents the rate-limiting step in telomerase expression and key roles for hTERT have been implied in cellular aging, immortalization, and transformation. Before the characterization of the promoter of hTERT in 1999, regulatory mechanisms suggested for this gene were limited to speculation. The successful cloning and characterization of the hTERT 5' gene regulatory region has enabled its formal investigation and analysis of potential mechanisms controlling hTERT expression. Although these studies have provided important information about hTERT gene regulation, there has been some confusion regarding the nucleotide boundaries of this region, the location, number, and importance of various transcription factor binding motifs, and the results of promoter activity assays. We feel that this uncertainty, combined with the sheer volume of recent publications on hTERT regulation, calls for consolidation and review. In this analysis we examine recent advances in the regulation of the hTERT gene and attempt to resolve discrepancies resulting from the nearly simultaneous nature of publications in this fast-moving area. Additionally, we aim to summarize the extant knowledge of hTERT gene regulation and its role in important biological processes such as cancer and aging.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11376932 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Cell Mol Life Sci. 1998 Jan;54(1):32-49.
Telomere tales: chromatin, telomerase and telomere function in Saccharomyces cerevisiae.
Lowell JE, Pillus L.
Department of Molecular, Cellular, and Development Biology, University of Colorado, Boulder 80309-0347, USA.
Unusual chromatin structures underlie epigenetic effects at the silent mating-type loci and telomeres in yeast. Many of the same genes appear to function in transcriptional silencing observed at both the silent mating-type loci and at telomeres. The observation that these loci are united by a requirement for shared factors suggests that the structure of chromatin at these regions is similar. Alteration of telomeric chromatin components affects regulation of transcription, telomeric length, recombination and chromosomal stability. Mutations in TLC1 and EST2, which both encode components of telomerase, cause identical phenotypes: progressive shortening of telomeric DNA, increased chromosome loss and eventually cell death. In this review, we examine the relationship between telomeric chromatin and telomere replication and discuss the possibility that telomerase itself is an integral part of telomeric chromatin structure.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9487385 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: 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]
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]
--------------------------------------------------------------------------------
2: 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]
--------------------------------------------------------------------------------
3: Crit Rev Oncol Hematol. 2005 May;54(2):85-93.
Telomerase: regulation, function and transformation.
Dong CK, Masutomi K, Hahn WC.
Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Work from several laboratories over the past decade indicates that the acquisition of constitutive telomerase expression is a critical step during the malignant transformation of human cells. Normal human cells transiently express low levels of telomerase, the ribonucleoprotein responsible for extending and maintaining telomeres, and exhibit telomere shortening after extended passage, whereas most cancers exhibit constitutive telomerase expression and maintain telomeres at stable lengths. These observations establish a direct connection between immortalization and stabilization of telomere structure. However, recent work suggests that telomerase also contributes to cancer development beyond its role in maintaining stable telomere lengths. In this review, we summarize recent observations that support the concept that telomerase plays multiple roles in facilitating human cell transformation.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15843091 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Sheng Li Ke Xue Jin Zhan. 2004 Apr;35(2):149-51.
[Recent advance of studies on telomerase function in stem cells]
[Article in Chinese]
Li J, Xie C, Pei XT.
Publication Types:
Review
PMID: 15285423 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
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]
--------------------------------------------------------------------------------
6: Cancer Lett. 2003 May 15;194(2):139-54.
Biochemical aspects of telomerase function.
Harrington L.
Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, 620 University Avenue, Rm. 932, Ontario M5G 2C1, Toronto, Canada. leah@uhnres.utoronto.ca <leah@uhnres.utoronto.ca>
Arthur Kornberg "never met a dull enzyme" (For the Love of Enzymes: The Odyssey of a Biochemist, Harvard University Press, 1989) and telomerase is no exception. Telomerase is a remarkable polymerase that uses an internal RNA template to reverse-transcribe telomere DNA, one nucleotide at a time, onto telomeric, G-rich single-stranded DNA. In the 17 years since its discovery, the characterization of telomerase enzyme components has uncovered a highly conserved family of telomerase reverse transcriptases that, together with the telomerase RNA, appear to comprise the enzymatic core of telomerase. While not as comprehensively understood as yet, some telomerase-associated proteins also serve crucial roles in telomerase function in vivo, such as telomerase ribonudeoprotein (RNP) assembly, recruitment to the telomere, and the coordination of DNA replication at the telomere. A selected overview of the biochemical properties of this unique enzyme, in vitro and in vivo, will be presented.
Publication Types:
Review
PMID: 12757972 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Tanpakushitsu Kakusan Koso. 2003 Mar;48(4 Suppl):501-7.
[Function of telomerase and heritable disease]
[Article in Japanese]
Nabetani A, Ishikawa F.
anabe@lif.kyoto-u.ac.jp
Publication Types:
Review
PMID: 12696160 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Pathol Oncol Res. 2001;7(3):161-70.
Telomerase: biological function and potential role in cancer management.
Chatziantoniou VD.
Semmelweis University, Budapest, Hungary. vchatzis@hotmail.com
Telomeres are the specialized ends of eukaryotic chromosomes, thought to have many functions, most importantly serving as a clock signaling entry into cellular senescence. These structures are maintained by the reverse transcriptase telomerase, a peculiar enzyme in both structure, since it contains its own template RNA and function, since it is inactivated in most normal tissues but activated in the vast majority of malignant tumors. These features have made telomerase a subject of intense investigation, both to understand its cellular role and regulation and to exploit its activation in cancer to develop drugs or diagnostic methods based on telomerase. This work gathers all the information currently available in the biological and clinical fields of telomerase research.
Publication Types:
Review
PMID: 11692141 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Gene. 2001 May 16;269(1-2):1-12.
Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT).
Poole JC, Andrews LG, Tollefsbol TO.
Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294-1170, USA.
Recent interest in the regulation of telomerase, the enzyme that maintains chromosomal termini, has lead to the discovery and characterization of the catalytic subunit of telomerase, hTERT. Many studies have suggested that the transcription of hTERT represents the rate-limiting step in telomerase expression and key roles for hTERT have been implied in cellular aging, immortalization, and transformation. Before the characterization of the promoter of hTERT in 1999, regulatory mechanisms suggested for this gene were limited to speculation. The successful cloning and characterization of the hTERT 5' gene regulatory region has enabled its formal investigation and analysis of potential mechanisms controlling hTERT expression. Although these studies have provided important information about hTERT gene regulation, there has been some confusion regarding the nucleotide boundaries of this region, the location, number, and importance of various transcription factor binding motifs, and the results of promoter activity assays. We feel that this uncertainty, combined with the sheer volume of recent publications on hTERT regulation, calls for consolidation and review. In this analysis we examine recent advances in the regulation of the hTERT gene and attempt to resolve discrepancies resulting from the nearly simultaneous nature of publications in this fast-moving area. Additionally, we aim to summarize the extant knowledge of hTERT gene regulation and its role in important biological processes such as cancer and aging.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11376932 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Cell Mol Life Sci. 1998 Jan;54(1):32-49.
Telomere tales: chromatin, telomerase and telomere function in Saccharomyces cerevisiae.
Lowell JE, Pillus L.
Department of Molecular, Cellular, and Development Biology, University of Colorado, Boulder 80309-0347, USA.
Unusual chromatin structures underlie epigenetic effects at the silent mating-type loci and telomeres in yeast. Many of the same genes appear to function in transcriptional silencing observed at both the silent mating-type loci and at telomeres. The observation that these loci are united by a requirement for shared factors suggests that the structure of chromatin at these regions is similar. Alteration of telomeric chromatin components affects regulation of transcription, telomeric length, recombination and chromosomal stability. Mutations in TLC1 and EST2, which both encode components of telomerase, cause identical phenotypes: progressive shortening of telomeric DNA, increased chromosome loss and eventually cell death. In this review, we examine the relationship between telomeric chromatin and telomere replication and discuss the possibility that telomerase itself is an integral part of telomeric chromatin structure.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9487385 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: 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]
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