Journal
EMBO JOURNAL
Volume 34, Issue 10, Pages 1371-1384Publisher
WILEY
DOI: 10.15252/embj.201490070
Keywords
aneuploidy; replication stress; senescence; telomerase; telomere
Categories
Funding
- Erich und Gertrud Roggenbuck Stiftung
- Deutsche Krebshilfe [10-2086-Gu 2]
- FP7 PEOPLE ITN [316354]
- European Research Council [323136, 322726]
- Austrian Science Fund [P23284]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [8866]
- Human Frontier Science Program (HFSP) [RGP 0014/2012]
- Association for International Cancer Research (AICR) [14-1331]
- Telethon [GGP12059]
- PRIN
- Italian Ministry of Education, Universities, and Research (MIUR) [2010M4NEFY_006]
- EPIGEN Project
- FIRC Fellowship
- Austrian Science Fund (FWF) [P23284] Funding Source: Austrian Science Fund (FWF)
- European Research Council (ERC) [323136] Funding Source: European Research Council (ERC)
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The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy-controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb-dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase-deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy-induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction.
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