Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions
| Autor: | Resham L Gurung, Marzia Fumagalli, Anitha Suram, Utz Herbig, Fabrizio d'Adda di Fagagna, Raffaella Di Micco, Aurora Cerutti, Neena Mirani, Haihe Ruan, Priyanka L. Patel, Virginia Boccardi, Jessica Kaplunov, Manoor Prakash Hande |
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| Rok vydání: | 2012 |
| Předmět: |
Genetics
Senescence 0303 health sciences General Immunology and Microbiology Oncogene Somatic cell General Neuroscience DNA replication Cancer Biology medicine.disease General Biochemistry Genetics and Molecular Biology 3. Good health Telomere 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis medicine Cancer research Telomerase reverse transcriptase Molecular Biology Cell aging 030304 developmental biology |
| Zdroj: | The EMBO Journal. 31:2839-2851 |
| ISSN: | 0261-4189 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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