Home LiteratureArticle Details
PMID: 19596237 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication.

Cell ·Vol. 138 ·No. 1 ·2009-07-10 ·Pages 90-103

Sfeir A, Kosiyatrakul ST, Hockemeyer D, MacRae SL, Karlseder J, Schildkraut CL, de Lange T

Abstract

Telomeres protect chromosome ends through the interaction of telomeric repeats with shelterin, a protein complex that represses DNA damage signaling and DNA repair reactions. The telomeric repeats are maintained by telomerase, which solves the end replication problem. We report that the TTAGGG repeat arrays of mammalian telomeres pose a challenge to the DNA replication machinery, giving rise to replication-dependent defects that resemble those of aphidicolin-induced common fragile sites. Gene deletion experiments showed that efficient duplication of telomeres requires the shelterin component TRF1. Without TRF1, telomeres activate the ATR kinase in S phase and show a fragile-site phenotype in metaphase. Single-molecule analysis of replicating telomeres showed that TRF1 promotes efficient replication of TTAGGG repeats and prevents fork stalling. Two helicases implicated in the removal of G4 DNA structures, BLM and RTEL1, were required to repress the fragile-telomere phenotype. These results identify a second telomere replication problem that is solved by the shelterin component TRF1.

MeSH Terms
Animals Aphidicolin Chromosome Fragile Sites Chromosomes, Mammalian/metabolism DNA Replication Humans Metaphase Mice Telomere/metabolism Telomeric Repeat Binding Protein 1/genetics,metabolism
Chemicals
Telomeric Repeat Binding Protein 1 Aphidicolin
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Sfeir Agnel
Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Kosiyatrakul Settapong T
Hockemeyer Dirk
MacRae Sheila L
Karlseder Jan
Schildkraut Carl L
de Lange Titia
References (67)
67 references, click to expand
  1. Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres.
    Cell. 2006 Jul 14;126(1):63-77 PMID: 16839877
  2. Cell cycle control of telomere protection and NHEJ revealed by a ts mutation in the DNA-binding domain of TRF2.
    Genes Dev. 2008 May 1;22(9):1221-30 PMID: 18451109
  3. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase.
    Curr Biol. 2006 Jul 11;16(13):1295-302 PMID: 16730176
  4. Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2.
    Hum Mol Genet. 2004 Sep 1;13(17):1919-32 PMID: 15229185
  5. Specific DNA replication mutations affect telomere length in Saccharomyces cerevisiae.
    Mol Cell Biol. 1996 Sep;16(9):4614-20 PMID: 8756617
  6. DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes.
    Hum Genet. 1984;67(2):136-42 PMID: 6430783
  7. Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length.
    Science. 2008 Jun 6;320(5881):1341-4 PMID: 18535244
  8. Increased frequencies of sister chromatid exchanges at common fragile sites (1)(q42) and (19)(q13).
    Hum Genet. 1989 Sep;83(2):145-7 PMID: 2476375
  9. POT1 as a terminal transducer of TRF1 telomere length control.
    Nature. 2003 Jun 26;423(6943):1013-8 PMID: 12768206
  10. A conserved G4 DNA binding domain in RecQ family helicases.
    J Mol Biol. 2006 May 12;358(4):1071-80 PMID: 16530788
  11. Distinct roles of TRF1 in the regulation of telomere structure and lengthening.
    J Biol Chem. 2008 Aug 29;283(35):23981-8 PMID: 18587156
  12. DNA damage foci at dysfunctional telomeres.
    Curr Biol. 2003 Sep 2;13(17):1549-56 PMID: 12956959
  13. The Bloom's syndrome helicase unwinds G4 DNA.
    J Biol Chem. 1998 Oct 16;273(42):27587-92 PMID: 9765292
  14. Telomestatin-induced telomere uncapping is modulated by POT1 through G-overhang extension in HT1080 human tumor cells.
    J Biol Chem. 2006 Dec 15;281(50):38721-9 PMID: 17050546
  15. ATR regulates fragile site stability.
    Cell. 2002 Dec 13;111(6):779-89 PMID: 12526805
  16. Massive horizontal gene transfer in bdelloid rotifers.
    Science. 2008 May 30;320(5880):1210-3 PMID: 18511688
  17. Replication timing of DNA sequences associated with human centromeres and telomeres.
    Mol Cell Biol. 1990 Dec;10(12):6348-55 PMID: 2247059
  18. Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein.
    Cell. 2004 Jun 25;117(7):873-86 PMID: 15210109
  19. Constitutive fragile sites and cancer.
    Science. 1984 Dec 7;226(4679):1199-204 PMID: 6239375
  20. Control of telomere length by the human telomeric protein TRF1.
    Nature. 1997 Feb 20;385(6618):740-3 PMID: 9034193
  21. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion.
    Nat Cell Biol. 2005 Jul;7(7):712-8 PMID: 15968270
  22. Human telomere structure and biology.
    Annu Rev Genomics Hum Genet. 2008;9:1-19 PMID: 18466090
  23. Control of human telomere length by TRF1 and TRF2.
    Mol Cell Biol. 2000 Mar;20(5):1659-68 PMID: 10669743
  24. The origin recognition complex localizes to telomere repeats and prevents telomere-circle formation.
    Curr Biol. 2007 Nov 20;17(22):1989-95 PMID: 18006317
  25. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance.
    Genes Dev. 2003 Mar 1;17(5):615-28 PMID: 12629044
  26. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II.
    Nat Cell Biol. 2008 Feb;10(2):228-36 PMID: 18157120
  27. BRCA1 is required for common-fragile-site stability via its G2/M checkpoint function.
    Mol Cell Biol. 2004 Aug;24(15):6701-9 PMID: 15254237
  28. Molecular and structural transactions at human DNA replication origins.
    Cell Cycle. 2007 Jul 15;6(14):1705-12 PMID: 17622799
  29. Heritable fragile sites in cancer.
    Nature. 1984 Apr 12-18;308(5960):607-8 PMID: 6709072
  30. Functional dissection of human and mouse POT1 proteins.
    Mol Cell Biol. 2009 Jan;29(2):471-82 PMID: 18955498
  31. Spontaneous and aphidicolin-sensitive fragile site 3cen co-localizes with the (TTAGGG)n telomeric sequence in Chinese hamster cells.
    Cytogenet Cell Genet. 1996;75(2-3):159-63 PMID: 9040784
  32. Semi-conservative DNA replication through telomeres requires Taz1.
    Nature. 2006 Apr 6;440(7085):824-8 PMID: 16598261
  33. Purification of proteins associated with specific genomic Loci.
    Cell. 2009 Jan 9;136(1):175-86 PMID: 19135898
  34. Structure of the TRFH dimerization domain of the human telomeric proteins TRF1 and TRF2.
    Mol Cell. 2001 Aug;8(2):351-61 PMID: 11545737
  35. Replication stress induces tumor-like microdeletions in FHIT/FRA3B.
    Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):246-51 PMID: 18162546
  36. A shared docking motif in TRF1 and TRF2 used for differential recruitment of telomeric proteins.
    Science. 2008 Feb 22;319(5866):1092-6 PMID: 18202258
  37. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1.
    Nature. 2007 Aug 30;448(7157):1068-71 PMID: 17687332
  38. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis.
    Nat Cell Biol. 2009 Jun;11(6):753-60 PMID: 19465922
  39. Shelterin: the protein complex that shapes and safeguards human telomeres.
    Genes Dev. 2005 Sep 15;19(18):2100-10 PMID: 16166375
  40. Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants.
    Am J Hum Genet. 2009 Mar;84(3):339-50 PMID: 19232554
  41. RTEL1 maintains genomic stability by suppressing homologous recombination.
    Cell. 2008 Oct 17;135(2):261-71 PMID: 18957201
  42. Normal human telomeres are not late replicating.
    Exp Cell Res. 1999 Sep 15;251(2):492-9 PMID: 10471333
  43. Involvement of human ORC and TRF2 in pre-replication complex assembly at telomeres.
    Genes Cells. 2008 Oct;13(10):1045-59 PMID: 18761675
  44. Visualization of DNA replication on individual Epstein-Barr virus episomes.
    Science. 2001 Dec 14;294(5550):2361-4 PMID: 11743204
  45. X-ray-induced telomeric instability in Atm-deficient mouse cells.
    Biochem Biophys Res Commun. 2004 Feb 27;315(1):51-8 PMID: 15013424
  46. Atm-deficient mice: a paradigm of ataxia telangiectasia.
    Cell. 1996 Jul 12;86(1):159-71 PMID: 8689683
  47. How shelterin protects mammalian telomeres.
    Annu Rev Genet. 2008;42:301-34 PMID: 18680434
  48. A human telomeric protein.
    Science. 1995 Dec 8;270(5242):1663-7 PMID: 7502076
  49. Chromosome fragile sites.
    Annu Rev Genet. 2007;41:169-92 PMID: 17608616
  50. G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3' telomeric overhang in cancer cells.
    Oncogene. 2006 Mar 23;25(13):1955-66 PMID: 16302000
  51. Dynamics of DNA replication in mammalian somatic cells: nucleotide pool modulates origin choice and interorigin spacing.
    Cell. 2003 Aug 8;114(3):385-94 PMID: 12914702
  52. A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination.
    Immunity. 1998 Sep;9(3):367-76 PMID: 9768756
  53. Evidence that instability within the FRA3B region extends four megabases.
    Oncogene. 2002 Dec 12;21(57):8713-22 PMID: 12483524
  54. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination.
    Nat Cell Biol. 2006 Aug;8(8):885-90 PMID: 16845382
  55. Progressive activation of DNA replication initiation in large domains of the immunoglobulin heavy chain locus during B cell development.
    Mol Cell. 2005 Nov 23;20(4):575-87 PMID: 16307921
  56. ORC binding to TRF2 stimulates OriP replication.
    EMBO Rep. 2006 Jul;7(7):716-21 PMID: 16799465
  57. Importance of TRF1 for functional telomere structure.
    J Biol Chem. 2004 Jan 9;279(2):1442-8 PMID: 14559908
  58. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends.
    Science. 2007 Nov 2;318(5851):798-801 PMID: 17916692
  59. Induction of sister chromatid exchanges at common fragile sites.
    Am J Hum Genet. 1987 Nov;41(5):882-90 PMID: 3674017
  60. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility.
    Nature. 2008 Nov 27;456(7221):524-8 PMID: 18931659
  61. Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres.
    Nature. 2007 Mar 8;446(7132):208-12 PMID: 17344853
  62. Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect.
    J Clin Invest. 2007 Nov;117(11):3236-47 PMID: 17932567
  63. Cancer predisposition caused by elevated mitotic recombination in Bloom mice.
    Nat Genet. 2000 Dec;26(4):424-9 PMID: 11101838
  64. G4 DNA unwinding by BLM and Sgs1p: substrate specificity and substrate-specific inhibition.
    Nucleic Acids Res. 2002 Sep 15;30(18):3954-61 PMID: 12235379
  65. CDC17: an essential gene that prevents telomere elongation in yeast.
    Cell. 1985 Aug;42(1):249-57 PMID: 3893744
  66. Targeted deletion reveals an essential function for the telomere length regulator Trf1.
    Mol Cell Biol. 2003 Sep;23(18):6533-41 PMID: 12944479
  67. Double telomeric signals on single chromatids revealed by FISH and PRINS.
    Ann Genet. 1999;42(4):202-9 PMID: 10674159
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2009.06.021
Published
2009-07-10
Pages
90-103
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2723738
Subset
IM
Grants
NCI NIH HHS · R01 CA076027-11 · United States
NIGMS NIH HHS · R37 GM049046 · United States
NIA NIH HHS · R01 AG016642 · United States
NIGMS NIH HHS · R37 GM049046-17 · United States
NCI NIH HHS · R01 CA076027 · United States
NIA NIH HHS · R01 AG016642-10 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2009.06.021 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2