Unbound MEDLINE

Removal of shelterin reveals the telomere end-protection problem.

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.

Links

  • Publisher Full Text
  • Authors

    Sfeir A, de Lange T

    Institution

    Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

    Source

    Science (New York, N.Y.) 336:6081 2012 May 4 pg 593-7

    MeSH

    Animals
    Antigens, Nuclear
    Cell Cycle
    Cell Cycle Proteins
    Cells, Cultured
    Chromosomal Proteins, Non-Histone
    DNA Breaks, Double-Stranded
    DNA End-Joining Repair
    DNA Ligases
    DNA Repair
    DNA-Binding Proteins
    Homologous Recombination
    Mice
    Mice, Knockout
    Poly(ADP-ribose) Polymerases
    Protein-Serine-Threonine Kinases
    Signal Transduction
    Telomere
    Telomere Homeostasis
    Telomere-Binding Proteins
    Telomeric Repeat Binding Protein 1
    Telomeric Repeat Binding Protein 2
    Tumor Suppressor Proteins

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22556254