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Multiple roles for MRE11 at uncapped telomeres

Progressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response as a result of a cell’s inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia... Full description

Journal Title: Nature 2009-08-13, Vol.460 (7257), p.914-918
Main Author: Deng, Yibin
Other Authors: Guo, Xiaolan , Chang, Sandy , Ferguson, David O
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: London: Nature Publishing Group
ID: ISSN: 0028-0836
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2760383
title: Multiple roles for MRE11 at uncapped telomeres
format: Article
creator:
  • Deng, Yibin
  • Guo, Xiaolan
  • Chang, Sandy
  • Ferguson, David O
subjects:
  • Alleles
  • Animals
  • Article
  • Ataxia Telangiectasia Mutated Proteins
  • ATP-Binding Cassette Transporters - genetics
  • ATP-Binding Cassette Transporters - metabolism
  • Biological and medical sciences
  • Cell Cycle Proteins - genetics
  • Cell Cycle Proteins - metabolism
  • Cell Line
  • Chromosomal Proteins, Non-Histone
  • Chromosome Aberrations
  • coenzymes (carbohydrates)
  • DNA Damage
  • DNA Ligase ATP
  • DNA Ligases - metabolism
  • DNA Repair Enzymes - deficiency
  • DNA Repair Enzymes - genetics
  • DNA Repair Enzymes - metabolism
  • DNA-Binding Proteins - deficiency
  • DNA-Binding Proteins - genetics
  • DNA-Binding Proteins - metabolism
  • enzymes
  • Fibroblasts
  • Fundamental and applied biological sciences. Psychology
  • Intracellular Signaling Peptides and Proteins - metabolism
  • Mice
  • Molecular and cellular biology
  • Molecular genetics
  • MRE11 Homologue Protein
  • Mutagenesis. Repair
  • Nuclear Proteins - deficiency
  • Nuclear Proteins - genetics
  • Nuclear Proteins - metabolism
  • Physiological aspects
  • Protein-Serine-Threonine Kinases - metabolism
  • Research
  • Telomere - genetics
  • Telomere - metabolism
  • Telomeres
  • Telomeric Repeat Binding Protein 2 - deficiency
  • Telomeric Repeat Binding Protein 2 - metabolism
  • Tumor Suppressor p53-Binding Protein 1
  • Tumor Suppressor Proteins - metabolism
ispartof: Nature, 2009-08-13, Vol.460 (7257), p.914-918
description: Progressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response as a result of a cell’s inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia and Rad3-related (ATR) kinase-dependent DNA damage response pathways, and promotes efficient non-homologous end-joining (NHEJ) of dysfunctional telomeres. The mammalian MRE11–RAD50–NBS1 (MRN; NBS1 is also known as NBN) complex interacts with ATM to sense chromosomal double-strand breaks and coordinate global DNA damage responses. Although the MRN complex accumulates at dysfunctional telomeres, it is not known whether mammalian MRN promotes repair at these sites. Here we address this question by using mouse alleles that either inactivate the entire MRN complex or eliminate only the nuclease activities of MRE11 (ref. 8). We show that cells lacking MRN do not activate ATM when telomeric repeat binding factor 2 (TRF2) is removed from telomeres, and ligase 4 (LIG4)-dependent chromosome end-to-end fusions are markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Notably, although cells deficient for MRE11 nuclease activity efficiently activate ATM and recruit 53BP1 (also known as TP53BP1) to deprotected telomeres, the 3′ telomeric overhang persists to prevent NHEJ-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3′ overhang in the setting of MRE11 nuclease deficiency restores LIG4-dependent chromosome fusions. Our data indicate a critical role for the MRN complex in sensing dysfunctional telomeres, and show that in the absence of TRF2, MRE11 nuclease activity removes the 3′ telomeric overhang to promote chromosome fusions. MRE11 can also protect newly replicated leading strand telomeres from NHEJ by promoting 5′ strand resection to generate POT1a–TPP1-bound 3′ overhangs.
language: eng
source:
identifier: ISSN: 0028-0836
fulltext: no_fulltext
issn:
  • 0028-0836
  • 1476-4687
url: Link


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descriptionProgressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response as a result of a cell’s inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia and Rad3-related (ATR) kinase-dependent DNA damage response pathways, and promotes efficient non-homologous end-joining (NHEJ) of dysfunctional telomeres. The mammalian MRE11–RAD50–NBS1 (MRN; NBS1 is also known as NBN) complex interacts with ATM to sense chromosomal double-strand breaks and coordinate global DNA damage responses. Although the MRN complex accumulates at dysfunctional telomeres, it is not known whether mammalian MRN promotes repair at these sites. Here we address this question by using mouse alleles that either inactivate the entire MRN complex or eliminate only the nuclease activities of MRE11 (ref. 8). We show that cells lacking MRN do not activate ATM when telomeric repeat binding factor 2 (TRF2) is removed from telomeres, and ligase 4 (LIG4)-dependent chromosome end-to-end fusions are markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Notably, although cells deficient for MRE11 nuclease activity efficiently activate ATM and recruit 53BP1 (also known as TP53BP1) to deprotected telomeres, the 3′ telomeric overhang persists to prevent NHEJ-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3′ overhang in the setting of MRE11 nuclease deficiency restores LIG4-dependent chromosome fusions. Our data indicate a critical role for the MRN complex in sensing dysfunctional telomeres, and show that in the absence of TRF2, MRE11 nuclease activity removes the 3′ telomeric overhang to promote chromosome fusions. MRE11 can also protect newly replicated leading strand telomeres from NHEJ by promoting 5′ strand resection to generate POT1a–TPP1-bound 3′ overhangs.
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subjectAlleles ; Animals ; Article ; Ataxia Telangiectasia Mutated Proteins ; ATP-Binding Cassette Transporters - genetics ; ATP-Binding Cassette Transporters - metabolism ; Biological and medical sciences ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell Line ; Chromosomal Proteins, Non-Histone ; Chromosome Aberrations ; coenzymes (carbohydrates) ; DNA Damage ; DNA Ligase ATP ; DNA Ligases - metabolism ; DNA Repair Enzymes - deficiency ; DNA Repair Enzymes - genetics ; DNA Repair Enzymes - metabolism ; DNA-Binding Proteins - deficiency ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; enzymes ; Fibroblasts ; Fundamental and applied biological sciences. Psychology ; Intracellular Signaling Peptides and Proteins - metabolism ; Mice ; Molecular and cellular biology ; Molecular genetics ; MRE11 Homologue Protein ; Mutagenesis. Repair ; Nuclear Proteins - deficiency ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Physiological aspects ; Protein-Serine-Threonine Kinases - metabolism ; Research ; Telomere - genetics ; Telomere - metabolism ; Telomeres ; Telomeric Repeat Binding Protein 2 - deficiency ; Telomeric Repeat Binding Protein 2 - metabolism ; Tumor Suppressor p53-Binding Protein 1 ; Tumor Suppressor Proteins - metabolism
ispartofNature, 2009-08-13, Vol.460 (7257), p.914-918
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descriptionProgressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response as a result of a cell’s inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia and Rad3-related (ATR) kinase-dependent DNA damage response pathways, and promotes efficient non-homologous end-joining (NHEJ) of dysfunctional telomeres. The mammalian MRE11–RAD50–NBS1 (MRN; NBS1 is also known as NBN) complex interacts with ATM to sense chromosomal double-strand breaks and coordinate global DNA damage responses. Although the MRN complex accumulates at dysfunctional telomeres, it is not known whether mammalian MRN promotes repair at these sites. Here we address this question by using mouse alleles that either inactivate the entire MRN complex or eliminate only the nuclease activities of MRE11 (ref. 8). We show that cells lacking MRN do not activate ATM when telomeric repeat binding factor 2 (TRF2) is removed from telomeres, and ligase 4 (LIG4)-dependent chromosome end-to-end fusions are markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Notably, although cells deficient for MRE11 nuclease activity efficiently activate ATM and recruit 53BP1 (also known as TP53BP1) to deprotected telomeres, the 3′ telomeric overhang persists to prevent NHEJ-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3′ overhang in the setting of MRE11 nuclease deficiency restores LIG4-dependent chromosome fusions. Our data indicate a critical role for the MRN complex in sensing dysfunctional telomeres, and show that in the absence of TRF2, MRE11 nuclease activity removes the 3′ telomeric overhang to promote chromosome fusions. MRE11 can also protect newly replicated leading strand telomeres from NHEJ by promoting 5′ strand resection to generate POT1a–TPP1-bound 3′ overhangs.
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30Mutagenesis. Repair
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32Nuclear Proteins - genetics
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35Protein-Serine-Threonine Kinases - metabolism
36Research
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38Telomere - metabolism
39Telomeres
40Telomeric Repeat Binding Protein 2 - deficiency
41Telomeric Repeat Binding Protein 2 - metabolism
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43Tumor Suppressor Proteins - metabolism
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0These authors contributed equally to this work.
1Present address: Section of Cancer Genetics, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
2Y.D. designed and guided all experiments, helped write the paper and generated figures. X.G. performed all the experiments presented. D.F. provided Mre11 mouse cell lines for this study and assisted in the interpretation of results. S.C. conceived this study, analyzed and interpreted the data, wrote the paper and finalized the figures.
3Author Contributions
abstractProgressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response as a result of a cell’s inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia and Rad3-related (ATR) kinase-dependent DNA damage response pathways, and promotes efficient non-homologous end-joining (NHEJ) of dysfunctional telomeres. The mammalian MRE11–RAD50–NBS1 (MRN; NBS1 is also known as NBN) complex interacts with ATM to sense chromosomal double-strand breaks and coordinate global DNA damage responses. Although the MRN complex accumulates at dysfunctional telomeres, it is not known whether mammalian MRN promotes repair at these sites. Here we address this question by using mouse alleles that either inactivate the entire MRN complex or eliminate only the nuclease activities of MRE11 (ref. 8). We show that cells lacking MRN do not activate ATM when telomeric repeat binding factor 2 (TRF2) is removed from telomeres, and ligase 4 (LIG4)-dependent chromosome end-to-end fusions are markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Notably, although cells deficient for MRE11 nuclease activity efficiently activate ATM and recruit 53BP1 (also known as TP53BP1) to deprotected telomeres, the 3′ telomeric overhang persists to prevent NHEJ-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3′ overhang in the setting of MRE11 nuclease deficiency restores LIG4-dependent chromosome fusions. Our data indicate a critical role for the MRN complex in sensing dysfunctional telomeres, and show that in the absence of TRF2, MRE11 nuclease activity removes the 3′ telomeric overhang to promote chromosome fusions. MRE11 can also protect newly replicated leading strand telomeres from NHEJ by promoting 5′ strand resection to generate POT1a–TPP1-bound 3′ overhangs.
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