Putative Telomere-recruiting Domain in the Catalytic Subunit of Human Telomerase

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2003 Apr 17

PMID 12697823

Citations 20

Authors

Blaine N Armbruster

Katherine T Etheridge

Dominique Broccoli

Christopher M Counter

Affiliations

Soon will be listed here.

Abstract

Telomerase, the enzyme that elongates telomeres, is essential to maintain telomere length and to immortalize most cancer cells. However, little is known about the regulation of this enzyme in higher eukaryotes. We previously described a domain in the hTERT telomerase catalytic subunit that is essential for telomere elongation and cell immortalization in vivo but dispensable for catalytic activity in vitro. Here, we show that fusions of hTERT containing different mutations in this domain to the telomere binding protein hTRF2 redirected the mutated hTERT to telomeres and rescued its in vivo functions. We suggest that this domain posttranscriptionally regulates telomerase function by targeting the enzyme to telomeres.

Citing Articles

Telomere elongation through hTERT immortalization leads to chromosome repositioning in control cells and genomic instability in Hutchinson-Gilford progeria syndrome fibroblasts, expressing a novel SUN1 isoform.

Bikkul M, Faragher R, Worthington G, Meinke P, Kerr A, Sammy A Genes Chromosomes Cancer. 2018; 58(6):341-356.

PMID: 30474255 PMC: 6590296. DOI: 10.1002/gcc.22711.

Direct observation of nucleic acid binding dynamics by the telomerase essential N-terminal domain.

Shastry S, Steinberg-Neifach O, Lue N, Stone M Nucleic Acids Res. 2018; 46(6):3088-3102.

PMID: 29474579 PMC: 5887506. DOI: 10.1093/nar/gky117.

The Insertion in Fingers Domain in Human Telomerase Can Mediate Enzyme Processivity and Telomerase Recruitment to Telomeres in a TPP1-Dependent Manner.

Chu T, DSouza Y, Autexier C Mol Cell Biol. 2015; 36(1):210-22.

PMID: 26503784 PMC: 4702596. DOI: 10.1128/MCB.00746-15.

Telomerase reverse transcriptase expression protects transformed human cells against DNA-damaging agents, and increases tolerance to chromosomal instability.

Fleisig H, Hukezalie K, Thompson C, Au-Yeung T, Ludlow A, Zhao C Oncogene. 2015; 35(2):218-27.

PMID: 25893297 DOI: 10.1038/onc.2015.75.

Identification of human TERT elements necessary for telomerase recruitment to telomeres.

Schmidt J, Dalby A, Cech T Elife. 2014; 3.

PMID: 25271372 PMC: 4359370. DOI: 10.7554/eLife.03563.

References

Etheridge K, Banik S, Armbruster B, Zhu Y, Terns R, Terns M . The nucleolar localization domain of the catalytic subunit of human telomerase. J Biol Chem. 2002; 277(27):24764-70. DOI: 10.1074/jbc.M201227200. View

Lundblad V, Szostak J . A mutant with a defect in telomere elongation leads to senescence in yeast. Cell. 1989; 57(4):633-43. DOI: 10.1016/0092-8674(89)90132-3. View

Stewart N, Bacchetti S . Expression of SV40 large T antigen, but not small t antigen, is required for the induction of chromosomal aberrations in transformed human cells. Virology. 1991; 180(1):49-57. DOI: 10.1016/0042-6822(91)90008-y. View

Murnane J, Sabatier L, Marder B, Morgan W . Telomere dynamics in an immortal human cell line. EMBO J. 1994; 13(20):4953-62. PMC: 395436. DOI: 10.1002/j.1460-2075.1994.tb06822.x. View

Chong L, van Steensel B, Broccoli D, Erdjument-Bromage H, Hanish J, Tempst P . A human telomeric protein. Science. 1995; 270(5242):1663-7. DOI: 10.1126/science.270.5242.1663. View

Holt S, Wright W, Shay J . Regulation of telomerase activity in immortal cell lines. Mol Cell Biol. 1996; 16(6):2932-9. PMC: 231287. DOI: 10.1128/MCB.16.6.2932. View

Evans S, Lundblad V . Est1 and Cdc13 as comediators of telomerase access. Science. 1999; 286(5437):117-20. DOI: 10.1126/science.286.5437.117. View

Lendvay T, Morris D, Sah J, Balasubramanian B, Lundblad V . Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. Genetics. 1996; 144(4):1399-412. PMC: 1207693. DOI: 10.1093/genetics/144.4.1399. View

van Steensel B, de Lange T . Control of telomere length by the human telomeric protein TRF1. Nature. 1997; 385(6618):740-3. DOI: 10.1038/385740a0. View

10.

Kim N, Wu F . Advances in quantification and characterization of telomerase activity by the telomeric repeat amplification protocol (TRAP). Nucleic Acids Res. 1997; 25(13):2595-7. PMC: 146790. DOI: 10.1093/nar/25.13.2595. View

11.

Shay J, Bacchetti S . A survey of telomerase activity in human cancer. Eur J Cancer. 1997; 33(5):787-91. DOI: 10.1016/S0959-8049(97)00062-2. View

12.

Broccoli D, Smogorzewska A, Chong L, de Lange T . Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat Genet. 1997; 17(2):231-5. DOI: 10.1038/ng1097-231. View

13.

Lingner J, Cech T, Hughes T, Lundblad V . Three Ever Shorter Telomere (EST) genes are dispensable for in vitro yeast telomerase activity. Proc Natl Acad Sci U S A. 1997; 94(21):11190-5. PMC: 23412. DOI: 10.1073/pnas.94.21.11190. View

14.

Weinrich S, Pruzan R, Ma L, Ouellette M, Tesmer V, Holt S . Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet. 1997; 17(4):498-502. DOI: 10.1038/ng1297-498. View

15.

van Steensel B, Smogorzewska A, de Lange T . TRF2 protects human telomeres from end-to-end fusions. Cell. 1998; 92(3):401-13. DOI: 10.1016/s0092-8674(00)80932-0. View

16.

Nakamura T, Cech T . Reversing time: origin of telomerase. Cell. 1998; 92(5):587-90. DOI: 10.1016/s0092-8674(00)81123-x. View

17.

Sedivy J . Can ends justify the means?: telomeres and the mechanisms of replicative senescence and immortalization in mammalian cells. Proc Natl Acad Sci U S A. 1998; 95(16):9078-81. PMC: 33878. DOI: 10.1073/pnas.95.16.9078. View

18.

Counter C, Hahn W, Wei W, Caddle S, Beijersbergen R, Lansdorp P . Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci U S A. 1998; 95(25):14723-8. PMC: 24516. DOI: 10.1073/pnas.95.25.14723. View

19.

Ouellette M, Aisner D, Wright W, Shay J . Telomerase activity does not always imply telomere maintenance. Biochem Biophys Res Commun. 1999; 254(3):795-803. DOI: 10.1006/bbrc.1998.0114. View

20.

Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T . p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science. 1999; 283(5406):1321-5. DOI: 10.1126/science.283.5406.1321. View