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Molecular and Cellular Biology, April 2005, p. 2708-2721, Vol. 25, No. 7
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.7.2708-2721.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Suppression of Alternative Lengthening of Telomeres by Sp100-Mediated Sequestration of the MRE11/RAD50/NBS1 Complex{dagger}

Wei-Qin Jiang, Ze-Huai Zhong, Jeremy D. Henson, Axel A. Neumann, Andy C.-M. Chang, and Roger R. Reddel*

Children's Medical Research Institute, Sydney, Australia

Received 14 October 2004/ Returned for modification 16 November 2004/ Accepted 5 January 2005

Approximately 10% of cancers overall use alternative lengthening of telomeres (ALT) instead of telomerase to prevent telomere shortening, and ALT is especially common in astrocytomas and various types of sarcomas. The hallmarks of ALT in telomerase-negative cancer cells include a unique pattern of telomere length heterogeneity, rapid changes in individual telomere lengths, and the presence of ALT-associated promyelocytic leukemia bodies (APBs) containing telomeric DNA and proteins involved in telomere binding, DNA replication, and recombination. The ALT mechanism appears to involve recombination-mediated DNA replication, but the molecular details are largely unknown. In telomerase-null Saccharomyces cerevisiae, an analogous survivor mechanism is dependent on the RAD50 gene. We demonstrate here that overexpression of Sp100, a constituent of promyelocytic leukemia nuclear bodies, sequestered the MRE11, RAD50, and NBS1 recombination proteins away from APBs. This resulted in repression of the ALT mechanism, as evidenced by progressive telomere shortening at 121 bp per population doubling, a rate within the range found in telomerase-negative normal cells, suppression of rapid telomere length changes, and suppression of APB formation. Spontaneously generated C-terminally truncated Sp100 that did not sequester the MRE11, RAD50, and NBS1 proteins failed to inhibit ALT. These findings identify for the first time proteins that are required for the ALT mechanism.

* Corresponding author. Mailing address: Children's Medical Research Institute, 214 Hawkesbury Rd., Westmead, NSW 2145, Australia. Phone: 61-2-9687-2800. Fax: 61-2-9687-2120. E-mail: rreddel{at}cmri.usyd.edu.au.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2005, p. 2708-2721, Vol. 25, No. 7
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.7.2708-2721.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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