Roles for RNA in Telomerase Nucleotide and Repeat Addition Processivity

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2003 Jun 25

PMID 12820978

Citations 51

Authors

Cary K Lai

Michael C Miller

Kathleen Collins

Affiliations

Soon will be listed here.

Abstract

Telomerase is a ribonucleoprotein reverse transcriptase with two subunits critical for catalytic activity, the protein telomerase reverse transcriptase (TERT) and telomerase RNA. In this study, we establish additional roles of the telomerase RNA subunit by demonstrating that RNA motifs stimulate the processivity of nucleotide and repeat addition. These functions are both functionally and physically separable from the roles of other RNA motifs in establishing a properly defined template. Binding of Tetrahymena telomerase RNA stem IV to TERT enhances nucleotide addition processivity, while a cooperation of the RNA pseudoknot and stem IV promotes repeat addition processivity. The low processivity of DNA synthesis by telomerase ribonucleoproteins lacking the pseudoknot and/or stem IV can be rescued by addition of the deleted region in trans. These findings demonstrate RNA elements with roles in telomerase elongation processivity that are distinct from RNA elements that specify the internal template.

Citing Articles

The role of ceranib-2 and its nanoform on the decrease of telomerase levels in human non-small cell cancer.

Cengiz M, Sezer C, Gur B, Bayrakdar A, Izgordu H, Alanyali F Mol Biol Rep. 2024; 51(1):889.

PMID: 39105852 DOI: 10.1007/s11033-024-09838-2.

Repositioning anticancer drugs as novel COVID-19 antivirals: targeting structural and functional similarities between viral proteins and cancer.

Low Z, Yip A, Lal S Expert Rev Mol Med. 2022; :1-23.

PMID: 35450545 PMC: 9114731. DOI: 10.1017/erm.2022.11.

Structural biology of human telomerase: progress and prospects.

Nguyen T Biochem Soc Trans. 2021; 49(5):1927-1939.

PMID: 34623385 PMC: 8589416. DOI: 10.1042/BST20200042.

Molecular mechanisms of telomere biology disorders.

Grill S, Nandakumar J J Biol Chem. 2021; 296:100064.

PMID: 33482595 PMC: 7948428. DOI: 10.1074/jbc.REV120.014017.

Population Genomics on the Fly: Recent Advances in Drosophila.

Haudry A, Laurent S, Kapun M Methods Mol Biol. 2020; 2090:357-396.

PMID: 31975175 DOI: 10.1007/978-1-0716-0199-0_15.

References

Prescott J, Blackburn E . Telomerase RNA mutations in Saccharomyces cerevisiae alter telomerase action and reveal nonprocessivity in vivo and in vitro. Genes Dev. 1997; 11(4):528-40. DOI: 10.1101/gad.11.4.528. View

Bhattacharyya A, Blackburn E . A functional telomerase RNA swap in vivo reveals the importance of nontemplate RNA domains. Proc Natl Acad Sci U S A. 1997; 94(7):2823-7. PMC: 20280. DOI: 10.1073/pnas.94.7.2823. View

Lingner J, Hughes T, Shevchenko A, Mann M, Lundblad V, Cech T . Reverse transcriptase motifs in the catalytic subunit of telomerase. Science. 1997; 276(5312):561-7. DOI: 10.1126/science.276.5312.561. View

Hammond P, Cech T . dGTP-dependent processivity and possible template switching of euplotes telomerase. Nucleic Acids Res. 1997; 25(18):3698-704. PMC: 146957. DOI: 10.1093/nar/25.18.3698. View

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

Roy J, Fulton T, Blackburn E . Specific telomerase RNA residues distant from the template are essential for telomerase function. Genes Dev. 1998; 12(20):3286-300. PMC: 317211. DOI: 10.1101/gad.12.20.3286. View

Licht J, Collins K . Telomerase RNA function in recombinant Tetrahymena telomerase. Genes Dev. 1999; 13(9):1116-25. PMC: 316941. DOI: 10.1101/gad.13.9.1116. View

Bosoy D, Lue N . Functional analysis of conserved residues in the putative "finger" domain of telomerase reverse transcriptase. J Biol Chem. 2001; 276(49):46305-12. DOI: 10.1074/jbc.M108168200. View

Peng Y, Mian I, Lue N . Analysis of telomerase processivity: mechanistic similarity to HIV-1 reverse transcriptase and role in telomere maintenance. Mol Cell. 2001; 7(6):1201-11. DOI: 10.1016/s1097-2765(01)00268-4. View

10.

Sperger J, Cech T . A stem-loop of Tetrahymena telomerase RNA distant from the template potentiates RNA folding and telomerase activity. Biochemistry. 2001; 40(24):7005-16. DOI: 10.1021/bi0103359. View

11.

Hardy C, SCHULTZ C, Collins K . Requirements for the dGTP-dependent repeat addition processivity of recombinant Tetrahymena telomerase. J Biol Chem. 2000; 276(7):4863-71. DOI: 10.1074/jbc.M005158200. View

12.

Lai C, Mitchell J, Collins K . RNA binding domain of telomerase reverse transcriptase. Mol Cell Biol. 2001; 21(4):990-1000. PMC: 99554. DOI: 10.1128/MCB.21.4.990-1000.2001. View

13.

Blasco M . Identification of functional domains and dominant negative mutations in vertebrate telomerase RNA using an in vivo reconstitution system. J Biol Chem. 2000; 276(8):5856-65. DOI: 10.1074/jbc.M008419200. View

14.

Peterson S, Stellwagen A, Diede S, Singer M, Haimberger Z, Johnson C . The function of a stem-loop in telomerase RNA is linked to the DNA repair protein Ku. Nat Genet. 2001; 27(1):64-7. DOI: 10.1038/83778. View

15.

Blackburn E . The end of the (DNA) line. Nat Struct Biol. 2000; 7(10):847-50. DOI: 10.1038/79594. View

16.

Bryan T, Goodrich K, Cech T . Telomerase RNA bound by protein motifs specific to telomerase reverse transcriptase. Mol Cell. 2000; 6(2):493-9. DOI: 10.1016/s1097-2765(00)00048-4. View

17.

Mitchell J, Collins K . Human telomerase activation requires two independent interactions between telomerase RNA and telomerase reverse transcriptase. Mol Cell. 2000; 6(2):361-71. DOI: 10.1016/s1097-2765(00)00036-8. View

18.

Miller M, Liu J, Collins K . Template definition by Tetrahymena telomerase reverse transcriptase. EMBO J. 2000; 19(16):4412-22. PMC: 302041. DOI: 10.1093/emboj/19.16.4412. View

19.

Bryan T, Goodrich K, Cech T . A mutant of Tetrahymena telomerase reverse transcriptase with increased processivity. J Biol Chem. 2000; 275(31):24199-207. DOI: 10.1074/jbc.M003246200. View

20.

Moore M, Query C . Joining of RNAs by splinted ligation. Methods Enzymol. 2000; 317:109-23. DOI: 10.1016/s0076-6879(00)17009-0. View