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Science 336 (6081): 593-597

Copyright © 2012 by the American Association for the Advancement of Science

Removal of Shelterin Reveals the Telomere End-Protection Problem

Agnel Sfeir*, and Titia de Lange{dagger}

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.

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

* Present address: Developmental Genetics Program and Department of Cell Biology, Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.

{dagger} To whom correspondence should be addressed. E-mail: delange{at}mail.rockefeller.edu


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