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Cell cycle control of telomere protection and NHEJ revealed by a ts mutation in the DNA-binding domain of TRF2

Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA

TRF2 is a component of shelterin, the telomere-specific protein complex that prevents DNA damage signaling and inappropriate repair at the natural ends of mammalian chromosomes. We describe a temperature-sensitive (ts) mutation in the Myb/SANT DNA-binding domain of TRF2 that allows controlled and reversible telomere deprotection. At 32°C, TRF2ts was functional and rescued the lethality of TRF2 deletion from conditional TRF2^F/– mouse embryonic fibroblasts (MEFs). When shifted to the nonpermissive temperature (37°C), TRF2ts cells showed extensive telomere damage resulting in activation of the ATM kinase and nonhomologous end-joining (NHEJ) of chromosome ends. The inactivation of TRF2ts at 37°C was rapid and reversible, permitting induction of short periods (3–6 h) of telomere dysfunction in the G0, G1, and S/G2 phases of the cell cycle. The results indicate that both the induction of telomere dysfunction and the re-establishment of the protected state can take place throughout interphase. In contrast, the processing of dysfunctional telomeres by NHEJ occurred primarily in G1, being repressed in S/G2 in a cyclin-dependent kinase (CDK)-dependent manner.

[Keywords: DNA damage; NHEJ; TRF2; shelterin; telomere]]

Received November 14, 2007; revised version accepted March 10, 2008.

² Correspondending author.

E-MAIL delange{at}mail.rockefeller.edu; FAX (212) 327-7147.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1634008.

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