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