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Oncogene‐induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions
Author(s) -
Suram Anitha,
Kaplunov Jessica,
Patel Priyanka L,
Ruan Haihe,
Cerutti Aurora,
Boccardi Virginia,
Fumagalli Marzia,
Di Micco Raffaella,
Mirani Neena,
Gurung Resham Lal,
Hande Manoor Prakash,
d'Adda di Fagagna Fabrizio,
Herbig Utz
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2012.132
Subject(s) - medical school , library science , cancer , gerontology , medicine , medical education , computer science
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.