title: Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions.
abstract: In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction-induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS. Furthermore, we demonstrate that oncogenic signalling, frequently associated with initiating cancer growth in humans, dramatically affected telomere structure and function by causing telomeric replication stress, rapid and stochastic telomere attrition, and consequently telomere dysfunction in cells that lack hTERT activity. DNA replication stress induced by drugs also resulted in telomere dysfunction and cellular senescence in normal human cells, demonstrating that telomeric repeats indeed are hypersensitive to DNA replication stress. Our data reveal that TDIS, accelerated by oncogene-induced DNA replication stress, is a biological response of cells in human cancer precursor lesions and provide strong evidence that TDIS is a critical tumour suppressing mechanism in humans.
authors.affiliation: New Jersey Medical School-University Hospital Cancer Center, UMDNJ-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Anitha
authors.initials: A
authors.lastname: Suram
authors.forename: Jessica
authors.initials: J
authors.lastname: Kaplunov
authors.forename: Priyanka L
authors.initials: PL
authors.lastname: Patel
authors.forename: Haihe
authors.initials: H
authors.lastname: Ruan
authors.forename: Aurora
authors.initials: A
authors.lastname: Cerutti
authors.forename: Virginia
authors.initials: V
authors.lastname: Boccardi
authors.forename: Marzia
authors.initials: M
authors.lastname: Fumagalli
authors.forename: Raffaella
authors.initials: R
authors.lastname: Di Micco
authors.forename: Neena
authors.initials: N
authors.lastname: Mirani
authors.forename: Resham Lal
authors.initials: RL
authors.lastname: Gurung
authors.forename: Manoor Prakash
authors.initials: MP
authors.lastname: Hande
authors.forename: Fabrizio
authors.initials: F
authors.lastname: d'Adda di Fagagna
authors.forename: Utz
authors.initials: U
authors.lastname: Herbig
mesh_terms: D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D009857:Oncogenes / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011691:Puromycin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016615:Telomere / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D011500:Protein Synthesis Inhibitors; D011691:Puromycin