Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway
- Purnima R. Laud1,5,
- Asha S. Multani1,5,
- Susan M. Bailey2,5,
- Ling Wu1,
- Jin Ma1,
- Charles Kingsley1,
- Michel Lebel3,
- Sen Pathak1,
- Ronald A. DePinho4,7, and
- Sandy Chang1,6
- 1Department of Molecular Genetics, University of Texas, The M.D. Anderson Cancer Center, Houston, Texas 77030, USA; 2Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523, USA; 3Centre de Recherche en Cancérologie de l'Université Laval, Hôpital Hôtel-Dieu de Québec, Québec, Canada G1R 2J6; 4Department of Medical Oncology and Center for Applied Cancer Science, Dana-Farber Cancer Institute and Departments of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
Abstract
Werner Syndrome (WS) is characterized by premature aging, genomic instability, and cancer. The combined impact of WRN helicase deficiency and limiting telomere reserves is central to disease pathogenesis. Here, we report that cells doubly deficient for telomerase and WRN helicase show chromosomal aberrations and elevated recombination rates between telomeres of sister chromatids. Somatic reconstitution of WRN function, but not a WRN helicase-deficient mutant, abolished telomere sister chromatid exchange (T-SCE), indicating that WRN normally represses T-SCEs. Elevated T-SCE was associated with greater immortalization potential and resultant tumors maintained telomeres via the alternative lengthening of telomere (ALT) pathway. We propose that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.
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Footnotes
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Supplemental material is available at http://genesdev.org.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1321305.
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Corresponding authors.
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↵5 These authors contributed equally to this work.
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↵7 E-MAIL ron_depinho{at}dfci.harvard.edu; FAX (617) 632-6069.
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↵6 E-MAIL schang{at}mdanderson.org; FAX (713) 834-6319.
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- Accepted September 6, 2005.
- Received April 5, 2005.
- Cold Spring Harbor Laboratory Press
