Cell death during crisis is mediated by mitotic telomere deprotection

• Published in: Nature (London) 2015-06, Vol.522 (7557), p.492-496
• Main Authors: Hayashi, Makoto T., Cesare, Anthony J., Rivera, Teresa, Karlseder, Jan
• Format: Article
• Language: English
• Subjects: 13; 13/106; 14; 14/63; 631/67; 631/80/103/560; 631/80/641/2350; 631/80/82; Apoptosis; Cell cycle; Cell Cycle Checkpoints - genetics; Cell death; Cell Death - drug effects; Cell Death - genetics; Cell Line; Cellular Senescence; Chromosome Aberrations; Chromosomes; Chromosomes, Human - genetics; Chromosomes, Human - metabolism; Crises; DNA Damage; Fibroblasts; Gene Fusion - genetics; Genomic Instability; Humanities and Social Sciences; Humans; Kinases; letter; Mitosis - drug effects; Mitosis - genetics; Mortality; multidisciplinary; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Poisons; Science; Senescence; Telomerase; Telomerase - genetics; Telomerase - metabolism; Telomere - genetics; Telomere - metabolism; Telomeric Repeat Binding Protein 2 - deficiency; Telomeric Repeat Binding Protein 2 - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14513

Cells that bypass senescence in the absence of the p53 tumour suppressor protein have shortened telomeres that undergo fusion, and these fusions trigger mitotic arrest and cell death in crisis. DNA damage signal kills cancer cells in crisis Cells forming a tumour must overcome two barriers before becoming cancerous. The first is senescence and the second is a proliferative block known as crisis. Cells that escape senescence usually succumb during crisis, but it has not been clear what triggers cell death at that stage. Jan Karlseder and colleagues now demonstrate that cells that bypass senescence in the absence of p53 have shortened telomeres that undergo fusion, and these fusions trigger mitotic delay. During mitotic arrest telomeres are further deprotected and detected by the DNA damage machinery, which leads to cell death. These findings might offer a clinical opportunity, as exacerbation of mitotic telomere deprotection sensitizes cancer cells to mitotic drugs — but mitotic arrest has also been associated with genome instability and tumorigenesis in checkpoint-compromised cells. Tumour formation is blocked by two barriers: replicative senescence and crisis 1 . Senescence is triggered by short telomeres and is bypassed by disruption of tumour-suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die. Cells that escape crisis harbour unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remains unexplained. Here we show that human cells in crisis undergo spontaneous mitotic arrest, resulting in death during mitosis or in the following cell cycle. This phenotype is induced by loss of p53 function, and is suppressed by telomerase overexpression. Telomere fusions triggered mitotic arrest in p53-compromised non-crisis cells, indicating that such fusions are the underlying cause of cell death. Exacerbation of mitotic telomere deprotection by partial TRF2 (also known as TERF2 ) knockdown 2 increased the ratio of cells that died during mitotic arrest and sensitized cancer cells to mitotic poisons. We propose a crisis pathway wherein chromosome fusions induce mitotic arrest, resulting in mitotic telomere deprotection and cell death, thereby eliminating precancerous cells from the population.