Home LiteratureArticle Details
PMID: 22556254 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Removal of shelterin reveals the telomere end-protection problem.

Science (New York, N.Y.) ·Vol. 336 ·No. 6081 ·2012-05-04 ·Pages 593-7

Sfeir A, de Lange T

Abstract

The telomere end-protection problem is defined by the aggregate of DNA damage signaling and repair pathways that require repression at telomeres. To define the end-protection problem, we removed the whole shelterin complex from mouse telomeres through conditional deletion of TRF1 and TRF2 in nonhomologous end-joining (NHEJ) deficient cells. The data reveal two DNA damage response pathways not previously observed upon deletion of individual shelterin proteins. The shelterin-free telomeres are processed by microhomology-mediated alternative-NHEJ when Ku70/80 is absent and are attacked by nucleolytic degradation in the absence of 53BP1. The data establish that the end-protection problem is specified by six pathways [ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) signaling, classical-NHEJ, alt-NHEJ, homologous recombination, and resection] and show how shelterin acts with general DNA damage response factors to solve this problem.

MeSH Terms
Animals Antigens, Nuclear/genetics,metabolism Ataxia Telangiectasia Mutated Proteins Cell Cycle Cell Cycle Proteins/metabolism Cells, Cultured Chromosomal Proteins, Non-Histone/metabolism DNA Breaks, Double-Stranded DNA End-Joining Repair DNA Ligase ATP DNA Ligases/metabolism DNA Repair DNA-Binding Proteins/genetics,metabolism Homologous Recombination Ku Autoantigen Mice Mice, Knockout Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases/metabolism Poly-ADP-Ribose Binding Proteins Protein Serine-Threonine Kinases/metabolism Signal Transduction Telomere/metabolism,ultrastructure Telomere Homeostasis Telomere-Binding Proteins/genetics,metabolism Telomeric Repeat Binding Protein 1/genetics,metabolism Telomeric Repeat Binding Protein 2/genetics,metabolism Tumor Suppressor Proteins/metabolism Tumor Suppressor p53-Binding Protein 1 Xenopus Proteins
Chemicals
Antigens, Nuclear Cell Cycle Proteins Chromosomal Proteins, Non-Histone DNA-Binding Proteins Poly-ADP-Ribose Binding Proteins TRF2 protein, mouse Telomere-Binding Proteins Telomeric Repeat Binding Protein 1 Telomeric Repeat Binding Protein 2 Trp53bp1 protein, mouse Tumor Suppressor Proteins Tumor Suppressor p53-Binding Protein 1 Xenopus Proteins Parp1 protein, mouse Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases Atr protein, mouse Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases Xrcc6 protein, mouse Ku Autoantigen DNA Ligases DNA Ligase ATP DNA ligase III alpha protein, Xenopus
Authors & Affiliations
2 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.
de Lange Titia
References (30)
30 references, click to expand
  1. The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres.
    EMBO J. 2010 Aug 4;29(15):2598-610 PMID: 20588252
  2. Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4-ligase IV during chromosomal translocation formation.
    Nat Struct Mol Biol. 2010 Apr;17(4):410-6 PMID: 20208544
  3. 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
  4. Telomere protection by TPP1 is mediated by POT1a and POT1b.
    Mol Cell Biol. 2010 Feb;30(4):1059-66 PMID: 19995905
  5. Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4.
    J Exp Med. 2010 Feb 15;207(2):417-27 PMID: 20142431
  6. Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal.
    Science. 2010 Mar 26;327(5973):1657-61 PMID: 20339076
  7. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1.
    Nature. 2007 Aug 30;448(7157):1068-71 PMID: 17687332
  8. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication.
    Cell. 2009 Jul 10;138(1):90-103 PMID: 19596237
  9. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.
    J Med Chem. 2008 Oct 23;51(20):6581-91 PMID: 18800822
  10. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways.
    Nucleic Acids Res. 2006;34(21):6170-82 PMID: 17088286
  11. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility.
    Nature. 2008 Nov 27;456(7221):524-8 PMID: 18931659
  12. Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends.
    Cell. 2008 Sep 19;134(6):981-94 PMID: 18805091
  13. DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation.
    PLoS Genet. 2011 Jun;7(6):e1002080 PMID: 21655080
  14. How telomeres solve the end-protection problem.
    Science. 2009 Nov 13;326(5955):948-52 PMID: 19965504
  15. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks.
    Cell. 2010 Apr 16;141(2):243-54 PMID: 20362325
  16. Telomere protection by TPP1/POT1 requires tethering to TIN2.
    Mol Cell. 2011 Nov 18;44(4):647-59 PMID: 22099311
  17. 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
  18. Functional dissection of human and mouse POT1 proteins.
    Mol Cell Biol. 2009 Jan;29(2):471-82 PMID: 18955498
  19. The yeast Ku heterodimer is essential for protection of the telomere against nucleolytic and recombinational activities.
    Curr Biol. 1998 Jul 2;8(14):831-4 PMID: 9663392
  20. How shelterin protects mammalian telomeres.
    Annu Rev Genet. 2008;42:301-34 PMID: 18680434
  21. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice.
    Genes Dev. 2009 Sep 1;23(17):2060-75 PMID: 19679647
  22. DNA helicases Sgs1 and BLM promote DNA double-strand break resection.
    Genes Dev. 2008 Oct 15;22(20):2767-72 PMID: 18923075
  23. Yeast Ku as a regulator of chromosomal DNA end structure.
    Science. 1998 May 1;280(5364):741-4 PMID: 9563951
  24. IgH class switching and translocations use a robust non-classical end-joining pathway.
    Nature. 2007 Sep 27;449(7161):478-82 PMID: 17713479
  25. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination.
    Nat Cell Biol. 2006 Aug;8(8):885-90 PMID: 16845382
  26. The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies.
    Nucleic Acids Res. 2010 Oct;38(18):6065-77 PMID: 20483915
  27. Ku is required for telomeric C-rich strand maintenance but not for end-to-end chromosome fusions in Arabidopsis.
    Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):611-5 PMID: 12511598
  28. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.
    Nat Struct Mol Biol. 2010 Jun;17(6):688-95 PMID: 20453858
  29. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing.
    Nature. 2008 Oct 9;455(7214):770-4 PMID: 18806779
  30. Protection of telomeres by the Ku protein in fission yeast.
    Mol Biol Cell. 2000 Oct;11(10):3265-75 PMID: 11029034
Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1218498
Published
2012-05-04
Pages
593-7
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3477646
Subset
IM
Grants
NIGMS NIH HHS · R01 GM049046 · United States
NIA NIH HHS · AG016642 · United States
NIGMS NIH HHS · R37 GM049046 · United States
NIA NIH HHS · R01 AG016642 · United States
NCI NIH HHS · R01 CA076027 · United States
NIGMS NIH HHS · GM49046 · United States
External Links
PubMed source DOI: 10.1126/science.1218498 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: [email protected]

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