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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, Nuclear / genetics
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Antigens, Nuclear / metabolism
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle
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Cell Cycle Proteins / metabolism
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Cells, Cultured
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Chromosomal Proteins, Non-Histone / metabolism
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DNA Breaks, Double-Stranded
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DNA End-Joining Repair
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DNA Ligase ATP
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DNA Ligases / metabolism
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DNA Repair
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Homologous Recombination
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Ku Autoantigen
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Mice
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Mice, Knockout
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases / metabolism
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Poly-ADP-Ribose Binding Proteins
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction
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Telomere / metabolism*
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Telomere / ultrastructure
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Telomere Homeostasis*
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Telomere-Binding Proteins / genetics
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Telomere-Binding Proteins / metabolism*
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Telomeric Repeat Binding Protein 1 / genetics
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Telomeric Repeat Binding Protein 1 / metabolism
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Telomeric Repeat Binding Protein 2 / genetics
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Telomeric Repeat Binding Protein 2 / metabolism
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor p53-Binding Protein 1
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Xenopus Proteins
Substances
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Antigens, Nuclear
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Cell Cycle Proteins
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Poly-ADP-Ribose Binding Proteins
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TRF2 protein, mouse
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Telomere-Binding Proteins
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Telomeric Repeat Binding Protein 1
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Telomeric Repeat Binding Protein 2
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Trp53bp1 protein, mouse
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Tumor Suppressor Proteins
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Tumor Suppressor p53-Binding Protein 1
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Xenopus Proteins
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Parp1 protein, mouse
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Atr protein, mouse
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Xrcc6 protein, mouse
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Ku Autoantigen
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DNA Ligases
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DNA Ligase ATP
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DNA ligase III alpha protein, Xenopus