title: Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion.
abstract: 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.
authors.affiliation: Leibniz Institute of Age Research, Fritz Lipmann Institute e.V., Jena, Germany.
authors.forename: Jitendra K
authors.initials: JK
authors.lastname: Meena
authors.affiliation: IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan, Italy.
authors.forename: Aurora
authors.initials: A
authors.lastname: Cerutti
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Beichler
authors.affiliation: Leibniz Institute of Age Research, Fritz Lipmann Institute e.V., Jena, Germany.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Leibniz Institute of Age Research, Fritz Lipmann Institute e.V., Jena, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bruhn
authors.affiliation: Institute of Experimental Cancer Research, University of Ulm, Ulm, Germany.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Medical Systems Biology Unit, Ulm University, Ulm, Germany.
authors.forename: Johann M
authors.initials: JM
authors.lastname: Kraus
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.affiliation: Leibniz Institute of Age Research, Fritz Lipmann Institute e.V., Jena, Germany.
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: Leibniz Institute of Age Research, Fritz Lipmann Institute e.V., Jena, Germany Medical Systems Biology Unit, Ulm University, Ulm, Germany.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.affiliation: IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan, Italy Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: d'Adda di Fagagna
authors.affiliation: Leibniz Institute of Age Research, Fritz Lipmann Institute e.V., Jena, Germany cguenes@fli-leibniz.de klrudolph@fli-leibniz.de.
authors.forename: Cagatay
authors.initials: C
authors.lastname: Günes
authors.affiliation: Leibniz Institute of Age Research, Fritz Lipmann Institute e.V., Jena, Germany cguenes@fli-leibniz.de klrudolph@fli-leibniz.de.
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000782:Aneuploidy; D000818:Animals; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D019098:Telomerase
keywords: aneuploidy; replication stress; senescence; telomerase; telomere
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