title: Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis.
abstract: Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.
authors.affiliation: Institute for Molecular Oncology, University Medical Center, Göttingen, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Begus-Nahrmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartmann
authors.forename: Johann
authors.initials: J
authors.lastname: Kraus
authors.forename: Parisa
authors.initials: P
authors.lastname: Eshraghi
authors.forename: Annika
authors.initials: A
authors.lastname: Scheffold
authors.forename: Melanie
authors.initials: M
authors.lastname: Grieb
authors.forename: Volker
authors.initials: V
authors.lastname: Rasche
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Han-Wong
authors.initials: HW
authors.lastname: Lee
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D043171:Chromosomal Instability; D004249:DNA Damage; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000201:enzymology* / Q000235:genetics
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase