Removal of Shelterin Reveals the Telomere End-Protection Problem

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 nonhomo...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2012-05, Vol.336 (6081), p.593-597
Main Authors: Sfeir, Agnel, de Lange, Titia
Format: Article
Language:English
Subjects:
Animals
Antigens, Nuclear - genetics
Antigens, Nuclear - metabolism
Ataxia telangiectasia
Ataxia telangiectasia mutated protein
Ataxia Telangiectasia Mutated Proteins
Biological and medical sciences
Cell Cycle
Cell Cycle Proteins - metabolism
Cells, Cultured
Chromatin. Chromosome
Chromosomal Proteins, Non-Histone - metabolism
Chromosomes
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA End-Joining Repair
DNA Ligase ATP
DNA Ligases - metabolism
DNA Repair
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Fundamental and applied biological sciences. Psychology
Homologous Recombination
Ku Autoantigen
Lymphocytes
Mice
Mice, Knockout
Molecular and cellular biology
Molecular genetics
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases - metabolism
Poly-ADP-Ribose Binding Proteins
Protein-Serine-Threonine Kinases - metabolism
Quantification
Repression
Signal Transduction
Telomerase
Telomere - metabolism
Telomere - ultrastructure
Telomere Homeostasis
Telomere-Binding Proteins - genetics
Telomere-Binding Proteins - metabolism
Telomeres
Telomeric Repeat Binding Protein 1 - genetics
Telomeric Repeat Binding Protein 1 - metabolism
Telomeric Repeat Binding Protein 2 - genetics
Telomeric Repeat Binding Protein 2 - metabolism
Tumor Suppressor p53-Binding Protein 1
Tumor Suppressor Proteins - metabolism
Xenopus Proteins
Yeasts
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Summary: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 a Iter nati ve-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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1218498