title: The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase.
abstract: Telomeres, the physical ends of eukaryotes chromosomes are transcribed into telomeric repeat containing RNA (TERRA), a large non-coding RNA of unknown function, which forms an integral part of telomeric heterochromatin. TERRA molecules resemble in sequence the telomeric DNA substrate as they contain 5'-UUAGGG-3' repeats near their 3'-end which are complementary to the template sequence of telomerase RNA. Here we demonstrate that endogenous TERRA is bound to human telomerase in cell extracts. Using in vitro reconstituted telomerase and synthetic TERRA molecules we demonstrate that the 5'-UUAGGG-3' repeats of TERRA base pair with the RNA template of the telomerase RNA moiety (TR). In addition TERRA contacts the telomerase reverse transcriptase (TERT) protein subunit independently of hTR. In vitro studies further demonstrate that TERRA is not used as a telomerase substrate. Instead, TERRA acts as a potent competitive inhibitor for telomeric DNA in addition to exerting an uncompetitive mode of inhibition. Our data identify TERRA as a telomerase ligand and natural direct inhibitor of human telomerase. Telomerase regulation by the telomere substrate may be mediated via its transcription.
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Frontiers in Genetics National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Redon
authors.forename: Patrick
authors.initials: P
authors.lastname: Reichenbach
authors.forename: Joachim
authors.initials: J
authors.lastname: Lingner
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000378:metabolism; D022661:RNA, Untranslated / Q000737:chemistry / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016615:Telomere / Q000737:chemistry; D013698:Templates, Genetic
chemical_list: D008024:Ligands; D010455:Peptides; D022661:RNA, Untranslated; C509186:TERT protein, human; D019098:Telomerase
references.citation: Cell. 2004 Jan 23;116(2):273-9
references.pmid: 14744437
references.citation: Cell. 1985 Dec;43(2 Pt 1):405-13
references.pmid: 3907856
references.citation: Nat Cell Biol. 2008 Feb;10(2):228-36
references.pmid: 18157120
references.citation: EMBO J. 2001 Dec 17;20(24):6958-68
references.pmid: 11742973
references.citation: Curr Biol. 2003 Apr 15;13(8):698-704
references.pmid: 12699629
references.citation: Nucleic Acids Res. 2001 Jun 1;29(11):2268-75
references.pmid: 11376145
references.citation: EMBO J. 2009 Sep 2;28(17):2503-10
references.pmid: 19629047
references.citation: Mol Cell Biol. 2004 May;24(9):3720-33
references.pmid: 15082768
references.citation: Mol Cell. 2008 Nov 21;32(4):465-77
references.pmid: 19026778
references.citation: J Biol Chem. 2002 Mar 8;277(10):8538-44
references.pmid: 11751869
references.citation: Mol Cell Biol. 1997 Jan;17(1):296-308
references.pmid: 8972210
references.citation: Nat Genet. 1998 Jun;19(2):199-202
references.pmid: 9620782
references.citation: J Biol Chem. 2002 May 3;277(18):15566-72
references.pmid: 11854300
references.citation: Curr Biol. 2003 Apr 1;13(7):568-74
references.pmid: 12676087
references.citation: Science. 1994 Dec 23;266(5193):2011-5
references.pmid: 7605428
references.citation: Cell Cycle. 2008 May 1;7(9):1161-5
references.pmid: 18418035
references.citation: Mol Cell Biol. 2007 Apr;27(8):3226-40
references.pmid: 17296728
references.citation: Nat Methods. 2007 Oct;4(10):851-3
references.pmid: 17893679
references.citation: Nat Rev Genet. 2007 Apr;8(4):299-309
references.pmid: 17363977
references.citation: Mol Cell Biol. 2001 Sep;21(18):6151-60
references.pmid: 11509658
references.citation: Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12061-5
references.pmid: 7991584
references.citation: Science. 2007 Mar 30;315(5820):1850-3
references.pmid: 17395830
references.citation: Oncogene. 2002 Jan 21;21(4):580-3
references.pmid: 11850782
references.citation: Nucleic Acids Res. 2007;35(20):7011-22
references.pmid: 17940095
references.citation: Biochimie. 2008 Jan;90(1):93-107
references.pmid: 17868970
references.citation: EMBO J. 2006 Feb 8;25(3):565-74
references.pmid: 16424902
references.citation: J Biol Chem. 2005 Jul 15;280(28):26586-91
references.pmid: 15905172
references.citation: Mol Cell Biol. 2005 Jan;25(2):808-18
references.pmid: 15632080
references.citation: Science. 2007 Nov 2;318(5851):798-801
references.pmid: 17916692
references.citation: EMBO J. 2001 Jul 2;20(13):3526-34
references.pmid: 11432839
references.citation: Nat Struct Mol Biol. 2008 Aug;15(8):870-2
references.pmid: 18641663
references.citation: Science. 2009 Nov 13;326(5955):948-52
references.pmid: 19965504