Home LiteratureArticle Details
PMID: 15314656 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response.

PLoS biology ·Vol. 2 ·No. 8 ·2004-08-00 ·Pages E240

Karlseder J, Hoke K, Mirzoeva OK, Bakkenist C, Kastan MB, Petrini JH, de Lange T

Abstract

The telomeric protein TRF2 is required to prevent mammalian telomeres from activating DNA damage checkpoints. Here we show that overexpression of TRF2 affects the response of the ATM kinase to DNA damage. Overexpression of TRF2 abrogated the cell cycle arrest after ionizing radiation and diminished several other readouts of the DNA damage response, including phosphorylation of Nbs1, induction of p53, and upregulation of p53 targets. TRF2 inhibited autophosphorylation of ATM on S1981, an early step in the activation of this kinase. A region of ATM containing S1981 was found to directly interact with TRF2 in vitro, and ATM immunoprecipitates contained TRF2. We propose that TRF2 has the ability to inhibit ATM activation at telomeres. Because TRF2 is abundant at chromosome ends but not elsewhere in the nucleus, this mechanism of checkpoint control could specifically block a DNA damage response at telomeres without affecting the surveillance of chromosome internal damage.

MeSH Terms
Ataxia Telangiectasia Mutated Proteins Cell Cycle Cell Cycle Proteins/metabolism Cell Line, Tumor Chromosomes/ultrastructure DNA Damage DNA-Binding Proteins/metabolism Dimerization Enzyme Activation Glutathione Transferase/metabolism Humans Immunoblotting Immunoprecipitation Nuclear Proteins/physiology Phosphorylation Protein Binding Protein Serine-Threonine Kinases/metabolism Radiation, Ionizing TATA Box Binding Protein-Like Proteins/physiology Telomere/ultrastructure Telomeric Repeat Binding Protein 2 Transfection Tumor Suppressor Protein p53/metabolism Tumor Suppressor Proteins/metabolism Up-Regulation
Chemicals
Cell Cycle Proteins DNA-Binding Proteins NBN protein, human Nuclear Proteins TATA Box Binding Protein-Like Proteins TERF2 protein, human Telomeric Repeat Binding Protein 2 Tumor Suppressor Protein p53 Tumor Suppressor Proteins Glutathione Transferase ATM protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Karlseder Jan
Laboratory for Cell Biology and Genetics, Rockefeller University, New York, USA.
Hoke Kristina
Mirzoeva Olga K
Bakkenist Christopher
Kastan Michael B
Petrini John H J
de Lange Titia
Conflict of Interest

The authors have declared that no conflicts of interest exist.

References (40)
40 references, click to expand
  1. The many substrates and functions of ATM.
    Nat Rev Mol Cell Biol. 2000 Dec;1(3):179-86 PMID: 11252893
  2. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing.
    Nature. 2003 Feb 6;421(6923):643-8 PMID: 12540856
  3. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer.
    Ann Neurol. 1991 Mar;29(3):241-51 PMID: 2042940
  4. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2.
    Science. 1999 Feb 26;283(5406):1321-5 PMID: 10037601
  5. Crystal structure of the Oxytricha nova telomere end binding protein complexed with single strand DNA.
    Cell. 1998 Dec 23;95(7):963-74 PMID: 9875850
  6. Structure of the TRFH dimerization domain of the human telomeric proteins TRF1 and TRF2.
    Mol Cell. 2001 Aug;8(2):351-61 PMID: 11545737
  7. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
    Nature. 2003 Jan 30;421(6922):499-506 PMID: 12556884
  8. ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes.
    Mol Cell. 2003 Dec;12(6):1489-98 PMID: 14690602
  9. Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint.
    Mol Cell Biol. 1995 Nov;15(11):6128-38 PMID: 7565765
  10. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres.
    Nat Genet. 2000 Jul;25(3):347-52 PMID: 10888888
  11. Genetic control of telomere integrity in Schizosaccharomyces pombe: rad3(+) and tel1(+) are parts of two regulatory networks independent of the downstream protein kinases chk1(+) and cds1(+).
    Genetics. 1999 Aug;152(4):1501-12 PMID: 10430579
  12. TRF2 recruits the Werner syndrome (WRN) exonuclease for processing of telomeric DNA.
    Oncogene. 2004 Jan 8;23(1):149-56 PMID: 14712220
  13. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2.
    Nat Genet. 1997 Oct;17(2):231-5 PMID: 9326950
  14. The cellular response to DNA double-strand breaks: defining the sensors and mediators.
    Trends Cell Biol. 2003 Sep;13(9):458-62 PMID: 12946624
  15. A DNA damage checkpoint response in telomere-initiated senescence.
    Nature. 2003 Nov 13;426(6963):194-8 PMID: 14608368
  16. Requirement of the MRN complex for ATM activation by DNA damage.
    EMBO J. 2003 Oct 15;22(20):5612-21 PMID: 14532133
  17. Identification of human Rap1: implications for telomere evolution.
    Cell. 2000 May 26;101(5):471-83 PMID: 10850490
  18. ATM and related protein kinases: safeguarding genome integrity.
    Nat Rev Cancer. 2003 Mar;3(3):155-68 PMID: 12612651
  19. Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.
    Nature. 2000 May 25;405(6785):473-7 PMID: 10839544
  20. Pot1, the putative telomere end-binding protein in fission yeast and humans.
    Science. 2001 May 11;292(5519):1171-5 PMID: 11349150
  21. ATM-dependent phosphorylation of nibrin in response to radiation exposure.
    Nat Genet. 2000 May;25(1):115-9 PMID: 10802669
  22. Different telomere damage signaling pathways in human and mouse cells.
    EMBO J. 2002 Aug 15;21(16):4338-48 PMID: 12169636
  23. DNA damage foci at dysfunctional telomeres.
    Curr Biol. 2003 Sep 2;13(17):1549-56 PMID: 12956959
  24. ATM associates with and phosphorylates p53: mapping the region of interaction.
    Nat Genet. 1998 Dec;20(4):398-400 PMID: 9843217
  25. The Mre11 complex is required for ATM activation and the G2/M checkpoint.
    EMBO J. 2003 Dec 15;22(24):6610-20 PMID: 14657032
  26. Protection of mammalian telomeres.
    Oncogene. 2002 Jan 21;21(4):532-40 PMID: 11850778
  27. TRF2 protects human telomeres from end-to-end fusions.
    Cell. 1998 Feb 6;92(3):401-13 PMID: 9476899
  28. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.
    Nature. 2000 Apr 6;404(6778):613-7 PMID: 10766245
  29. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks.
    J Cell Biol. 2000 Dec 25;151(7):1381-90 PMID: 11134068
  30. Monoclonal antibodies generated against recombinant ATM support kinase activity.
    Hybridoma. 2000 Aug;19(4):317-21 PMID: 11001404
  31. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.
    Science. 1998 Sep 11;281(5383):1677-9 PMID: 9733515
  32. ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response.
    Nature. 2000 May 25;405(6785):477-82 PMID: 10839545
  33. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases.
    J Biol Chem. 2002 Oct 25;277(43):41110-9 PMID: 12181313
  34. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2.
    Curr Biol. 2002 Oct 1;12(19):1635-44 PMID: 12361565
  35. Control of human telomere length by TRF1 and TRF2.
    Mol Cell Biol. 2000 Mar;20(5):1659-68 PMID: 10669743
  36. T-loop assembly in vitro involves binding of TRF2 near the 3' telomeric overhang.
    EMBO J. 2001 Oct 1;20(19):5532-40 PMID: 11574485
  37. Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks.
    J Biol Chem. 2001 Aug 3;276(31):29282-91 PMID: 11375976
  38. Regulation of genome stability by TEL1 and MEC1, yeast homologs of the mammalian ATM and ATR genes.
    Genetics. 2002 Jun;161(2):493-507 PMID: 12072449
  39. Senescence induced by altered telomere state, not telomere loss.
    Science. 2002 Mar 29;295(5564):2446-9 PMID: 11923537
  40. Mammalian telomeres end in a large duplex loop.
    Cell. 1999 May 14;97(4):503-14 PMID: 10338214
Article Info
Journal
PLoS biology
Abbr.
PLoS Biol
ISSN
1545-7885
DOI
10.1371/journal.pbio.0020240
Published
2004-08-00
Epub
2004-00-17
Pages
E240
Language
English
Region
United States
NLM ID
101183755
PMCID
PMC509302
Subset
IM
Grants
NIGMS NIH HHS · R37 GM059413 · United States
NIGMS NIH HHS · GM07739 · United States
NIGMS NIH HHS · R01 GM049046 · United States
NIGMS NIH HHS · GM59413 · United States
NCI NIH HHS · CA21765 · United States
NIA NIH HHS · AG016642 · United States
NIGMS NIH HHS · GM56888 · United States
NIGMS NIH HHS · R37 GM049046 · United States
NCI NIH HHS · R01 CA071387 · United States
NIA NIH HHS · R01 AG016642 · United States
NCI NIH HHS · P30 CA021765 · United States
NIGMS NIH HHS · R01 GM059413 · United States
NIGMS NIH HHS · T32 GM007739 · United States
NIGMS NIH HHS · R01 GM056888 · United States
NCI NIH HHS · CA71387 · United States
NIGMS NIH HHS · GM49046 · United States
External Links
PubMed source DOI: 10.1371/journal.pbio.0020240 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