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Molecular and Cellular Biology, October 2009, p. 5540-5551, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00479-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Mre11 Complex and the Response to Dysfunctional Telomeres{triangledown}

Claire L. Attwooll,1 Müge Akpinar,1,2 and John H. J. Petrini1,3*

Molecular Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York,1 Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York,2 Weill Cornell Graduate School of Medical Science, New York, New York3

Received 13 April 2009/ Returned for modification 26 May 2009/ Accepted 3 August 2009

In this study, we examine the telomeric functions of the mammalian Mre11 complex by using hypomorphic Mre11 and Nbs1 mutants (Mre11ATLD1/ATLD1 and Nbs1{Delta}B/{Delta}B, respectively). No telomere shortening was observed in Mre11ATLD1/ATLD1 cells after extensive passage through culture, and the rate of telomere shortening in telomerase-deficient (Tert{Delta}/{Delta}) Mre11ATLD1/ATLD1 cells was the same as that in Tert{Delta}/{Delta} alone. Although telomeres from late-passage Mre11ATLD1/ATLD1 Tert{Delta}/{Delta} cells were as short as those from Tert{Delta}/{Delta}, the incidence of telomere fusions was reduced. This effect on fusions was also evident upon acute telomere dysfunction in Mre11ATLD1/ATLD1 and Nbs1{Delta}B/{Delta}B cells rendered Trf2 deficient by cre-mediated TRF2 inactivation than in wild-type cells. The residual fusions formed in Mre11 complex mutant cells exhibited a strong tendency toward chromatid fusions, with an almost complete bias for fusion of telomeres replicated by the leading strand. Finally, the response to acute telomere dysfunction was strongly impaired by Mre11 complex hypomorphism, as the formation of telomere dysfunction-induced DNA damage foci was reduced in both cre-infected Mre11ATLD1/ATLD1 Trf2F/{Delta} and Nbs1{Delta}B/{Delta}B Trf2F/F cells. These data indicate that the Mre11 complex influences the cellular response to telomere dysfunction, reminiscent of its influence on the response to interstitial DNA breaks, and suggest that it may promote telomeric DNA end processing during DNA replication.

* Corresponding author. Mailing address: Laboratory of Chromosome Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, RRL 901C Box 474, New York, NY 10021. Phone: (212) 639-2927. Fax: (646) 422-2062. E-mail: petrinij{at}mskcc.org

{triangledown} Published ahead of print on 10 August 2009.

Molecular and Cellular Biology, October 2009, p. 5540-5551, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00479-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • de Lange, T. (2009). How Telomeres Solve the End-Protection Problem. Science 326: 948-952 [Abstract] [Full Text]  


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