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Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex.
Mol Cell Biol. 2005 Apr; 25(7):2708-21.MC

Abstract

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.

Authors+Show Affiliations

Children's Medical Research Institute, 214 Hawkesbury Rd., Westmead, NSW 2145, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15767676

Citation

Jiang, Wei-Qin, et al. "Suppression of Alternative Lengthening of Telomeres By Sp100-mediated Sequestration of the MRE11/RAD50/NBS1 Complex." Molecular and Cellular Biology, vol. 25, no. 7, 2005, pp. 2708-21.
Jiang WQ, Zhong ZH, Henson JD, et al. Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex. Mol Cell Biol. 2005;25(7):2708-21.
Jiang, W. Q., Zhong, Z. H., Henson, J. D., Neumann, A. A., Chang, A. C., & Reddel, R. R. (2005). Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex. Molecular and Cellular Biology, 25(7), 2708-21.
Jiang WQ, et al. Suppression of Alternative Lengthening of Telomeres By Sp100-mediated Sequestration of the MRE11/RAD50/NBS1 Complex. Mol Cell Biol. 2005;25(7):2708-21. PubMed PMID: 15767676.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex. AU - Jiang,Wei-Qin, AU - Zhong,Ze-Huai, AU - Henson,Jeremy D, AU - Neumann,Axel A, AU - Chang,Andy C-M, AU - Reddel,Roger R, PY - 2005/3/16/pubmed PY - 2005/4/20/medline PY - 2005/3/16/entrez SP - 2708 EP - 21 JF - Molecular and cellular biology JO - Mol. Cell. Biol. VL - 25 IS - 7 N2 - 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. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/15767676/Suppression_of_alternative_lengthening_of_telomeres_by_Sp100_mediated_sequestration_of_the_MRE11/RAD50/NBS1_complex_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=15767676 DB - PRIME DP - Unbound Medicine ER -