Removal of shelterin reveals the telomere end-protection problem

Science. 2012 May 4;336(6081):593-7. doi: 10.1126/science.1218498.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Nuclear / genetics
  • Antigens, Nuclear / 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
  • DNA-Binding Proteins / 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*
  • Telomere / ultrastructure
  • Telomere Homeostasis*
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism*
  • 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 Proteins / metabolism
  • Tumor Suppressor p53-Binding Protein 1
  • Xenopus Proteins

Substances

  • 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