Report

Loss of Rap1 Induces Telomere Recombination in the Absence of NHEJ or a DNA Damage Signal

Science  26 Mar 2010:
Vol. 327, Issue 5973, pp. 1657-1661
DOI: 10.1126/science.1185100

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Shelterin the Ends

The ends of linear chromosomes suffer two problems: They cannot be replicated to their termini, resulting in loss of terminal sequences; and they can be mistakenly sensed as DNA double-strand breaks, activating DNA repair pathways that can result in serious genome derangement. These problems are solved by the addition of telomeres, repeat sequences at the ends of chromosomes, which are shielded by a protein complex called shelterin. Sfeir et al. (p. 1657) show that the mouse Rap1 protein, which is part of the shelterin complex and which binds to a second shelterin protein called TRF2, helps prevent telomeres undergoing unscheduled homologous recombination. Such recombination could threaten telomere integrity by generating sequence exchanges between sister telomeres resulting in critically shortened telomeres.

Abstract

Shelterin is an essential telomeric protein complex that prevents DNA damage signaling and DNA repair at mammalian chromosome ends. Here we report on the role of the TRF2-interacting factor Rap1, a conserved shelterin subunit of unknown function. We removed Rap1 from mouse telomeres either through gene deletion or by replacing TRF2 with a mutant that does not bind Rap1. Rap1 was dispensable for the essential functions of TRF2—repression of ATM kinase signaling and nonhomologous end joining (NHEJ)—and mice lacking telomeric Rap1 were viable and fertile. However, Rap1 was critical for the repression of homology-directed repair (HDR), which can alter telomere length. The data reveal that HDR at telomeres can take place in the absence of DNA damage foci and underscore the functional compartmentalization within shelterin.

  • * These authors contributed equally to this work.

  • Present address: Department of Molecular Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

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