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PMID: 21441540 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

G-quadruplex formation at the 3' end of telomere DNA inhibits its extension by telomerase, polymerase and unwinding by helicase.

Nucleic acids research ·Vol. 39 ·No. 14 ·2011-08-00 ·Pages 6229-37

Wang Q, Liu JQ, Chen Z, Zheng KW, Chen CY, Hao YH, Tan Z

Abstract

Telomere G-quadruplex is emerging as a promising anti-cancer target due to its inhibition to telomerase, an enzyme expressed in more than 85% tumors. Telomerase-mediated telomere extension and some other reactions require a free 3' telomere end in single-stranded form. G-quadruplex formation near the 3' end of telomere DNA can leave a 3' single-stranded tail of various sizes. How these terminal structures affect reactions at telomere end is not clear. In this work, we studied the 3' tail size-dependence of telomere extension by either telomerase or the alternative lengthening of telomere (ALT) mechanism as well as telomere G-quadruplex unwinding. We show that these reactions require a minimal tail of 8, 12 and 6 nt, respectively. Since we have shown that G-quadruplex tends to form at the farthest 3' distal end of telomere DNA leaving a tail of no more than 5 nt, these results imply that G-quadruplex formation may play a role in regulating reactions at the telomere ends and, as a result, serve as effective drug target for intervening telomere function.

MeSH Terms
DNA/chemistry DNA Polymerase I/metabolism G-Quadruplexes RecQ Helicases/metabolism Telomerase/metabolism Telomere/chemistry,metabolism
Chemicals
DNA Telomerase DNA Polymerase I Bloom syndrome protein RecQ Helicases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Wang Quan
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
Liu Jia-quan
Chen Zhao
Zheng Ke-wei
Chen Chang-yue
Hao Yu-Hua
Tan Zheng
References (40)
40 references, click to expand
  1. Quantitative telomeric overhang determination using a double-strand specific nuclease.
    Nucleic Acids Res. 2008 Feb;36(3):e14 PMID: 18073199
  2. The Bloom's syndrome helicase unwinds G4 DNA.
    J Biol Chem. 1998 Oct 16;273(42):27587-92 PMID: 9765292
  3. Specific association of human telomerase activity with immortal cells and cancer.
    Science. 1994 Dec 23;266(5193):2011-5 PMID: 7605428
  4. Human telomeric DNA forms parallel-stranded intramolecular G-quadruplex in K+ solution under molecular crowding condition.
    J Am Chem Soc. 2007 Sep 12;129(36):11185-91 PMID: 17705383
  5. Improved telomere detection using a telomere repeat probe (TTAGGG)n generated by PCR.
    Nucleic Acids Res. 1991 Sep 11;19(17):4780 PMID: 1891373
  6. Minimum length requirement of the alignment domain of human telomerase RNA to sustain catalytic activity in vitro.
    Nucleic Acids Res. 2002 Oct 15;30(20):4470-80 PMID: 12384594
  7. Human telomeric G-quadruplex: the current status of telomeric G-quadruplexes as therapeutic targets in human cancer.
    FEBS J. 2010 Mar;277(5):1118-25 PMID: 19951354
  8. Human telomerase catalyzes nucleolytic primer cleavage.
    Nucleic Acids Res. 2004 Apr 19;32(7):2171-80 PMID: 15096579
  9. Reconstitution of human telomerase activity in vitro.
    Curr Biol. 1998 Jan 29;8(3):177-80 PMID: 9443919
  10. Telomere control of replicative lifespan.
    Exp Gerontol. 1997 Jul-Oct;32(4-5):375-82 PMID: 9315442
  11. G-quadruplex structures: in vivo evidence and function.
    Trends Cell Biol. 2009 Aug;19(8):414-22 PMID: 19589679
  12. Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening.
    Cell. 1997 Mar 7;88(5):657-66 PMID: 9054505
  13. An exonuclease I hydrolysis assay for evaluating G-quadruplex stabilization by small molecules.
    Nucleic Acids Res. 2007;35(9):e68 PMID: 17426118
  14. Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo.
    Nat Struct Mol Biol. 2005 Oct;12(10):847-54 PMID: 16142245
  15. Normal human chromosomes have long G-rich telomeric overhangs at one end.
    Genes Dev. 1997 Nov 1;11(21):2801-9 PMID: 9353250
  16. Human telomeres have different overhang sizes at leading versus lagging strands.
    Mol Cell. 2006 Feb 3;21(3):427-35 PMID: 16455497
  17. Kinetics of base stacking-aided DNA hybridization.
    Chem Commun (Camb). 2008 Dec 28;(48):6600-2 PMID: 19057792
  18. A topological mechanism for TRF2-enhanced strand invasion.
    Nat Struct Mol Biol. 2007 Feb;14(2):147-54 PMID: 17220898
  19. RecQ helicases: caretakers of the genome.
    Nat Rev Cancer. 2003 Mar;3(3):169-78 PMID: 12612652
  20. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon.
    J Theor Biol. 1973 Sep 14;41(1):181-90 PMID: 4754905
  21. DNA structure-dependent recruitment of telomeric proteins to single-stranded/double-stranded DNA junctions.
    Biochem Biophys Res Commun. 2005 Mar 4;328(1):49-56 PMID: 15670749
  22. Alternative lengthening of telomeres in mammalian cells.
    Oncogene. 2002 Jan 21;21(4):598-610 PMID: 11850785
  23. Advances in quantification and characterization of telomerase activity by the telomeric repeat amplification protocol (TRAP).
    Nucleic Acids Res. 1997 Jul 1;25(13):2595-7 PMID: 9185569
  24. Inhibition of telomerase by G-quartet DNA structures.
    Nature. 1991 Apr 25;350(6320):718-20 PMID: 2023635
  25. Structure of hnRNP D complexed with single-stranded telomere DNA and unfolding of the quadruplex by heterogeneous nuclear ribonucleoprotein D.
    J Biol Chem. 2005 May 13;280(19):18862-70 PMID: 15734733
  26. Folding equilibrium constants of telomere G-quadruplexes in free state or associated with proteins determined by isothermal differential hybridization.
    Anal Chem. 2010 Nov 15;82(22):9469-75 PMID: 21028832
  27. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT.
    Nat Genet. 1997 Dec;17(4):498-502 PMID: 9398860
  28. Recognition of a chromosome truncation site associated with alpha-thalassaemia by human telomerase.
    Nature. 1991 Oct 3;353(6343):454-6 PMID: 1896089
  29. The Bloom's syndrome gene product is a 3'-5' DNA helicase.
    J Biol Chem. 1997 Dec 5;272(49):30611-4 PMID: 9388193
  30. G-quadruplex preferentially forms at the very 3' end of vertebrate telomeric DNA.
    Nucleic Acids Res. 2008 Mar;36(4):1200-8 PMID: 18158301
  31. Processive utilization of the human telomerase template: lack of a requirement for template switching.
    J Biol Chem. 2004 Dec 17;279(51):53770-81 PMID: 15456773
  32. Molecular crowding creates an essential environment for the formation of stable G-quadruplexes in long double-stranded DNA.
    Nucleic Acids Res. 2010 Jan;38(1):327-38 PMID: 19858105
  33. The effect of the TRF2 N-terminal and TRFH regions on telomeric G-quadruplex structures.
    Nucleic Acids Res. 2009 Apr;37(5):1541-54 PMID: 19139067
  34. G-quadruplex formation in human telomeric (TTAGGG)4 sequence with complementary strand in close vicinity under molecularly crowded condition.
    Nucleic Acids Res. 2007;35(11):3646-53 PMID: 17488850
  35. Detection of telomerase inhibitors based on g-quadruplex ligands by a modified telomeric repeat amplification protocol assay.
    Cancer Res. 2002 Jun 15;62(12):3365-8 PMID: 12067975
  36. In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei.
    Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8572-7 PMID: 11438689
  37. In vivo DNA analysis.
    Methods Mol Biol. 2001;148:175-219 PMID: 11357585
  38. G-quadruplex hinders translocation of BLM helicase on DNA: a real-time fluorescence spectroscopic unwinding study and comparison with duplex substrates.
    J Am Chem Soc. 2010 Aug 4;132(30):10521-7 PMID: 20614884
  39. Yeast telomerase subunit Est1p has guanine quadruplex-promoting activity that is required for telomere elongation.
    Nat Struct Mol Biol. 2010 Feb;17(2):202-9 PMID: 20098422
  40. G-quadruplexes induce apoptosis in tumor cells.
    Cancer Res. 2006 Dec 15;66(24):11808-16 PMID: 17178877
Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gkr164
Published
2011-08-00
Epub
2011-00-25
Pages
6229-37
Language
English
Region
England
NLM ID
0411011
PMCID
PMC3152327
Subset
IM
External Links
PubMed source DOI: 10.1093/nar/gkr164 PMC Full Text View journal details
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