Cell death during crisis is mediated by mitotic telomere deprotection

Abstract

Tumour formation is blocked by two barriers, replicative senescence and crisis1. 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 harbor unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remained elusive. We show that cells in crisis undergo spontaneous mitotic arrest, resulting in death during mitosis or in the following cell cycle. The phenotype was induced by loss of p53 function, and suppressed by telomerase overexpression. Telomere fusions triggered mitotic arrest in p53-compromised non-crisis cells, indicating such fusions as the underlying cause. Exacerbation of mitotic telomere deprotection by partial TRF2 knockdown2 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.

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

“…Our results confirm a critical role of the TP53 checkpoint in restricting the accumulation of widespread genomic mutations resulting from telomere dysfunction (Hartwell 1992;Hayashi et al 2015).…”

“…In a model of DNA replication-coupled repair, however, these loci represent the most likely sources of copy number variation, increasing local substrate availability at locations where repair and replication enzymes are already colocalized. As such, these loci may also present enhanced opportunity for fusion by replication-independent NHEJ as a means of rapid DSB repair, resulting in mitotic arrest (Hayashi et al 2015). Cell cycle regulation of template availability and processing may also affect the mechanism of telomere fusions (Escribano-Díaz et al 2013).…”

“…Conversely, telomere fusions mediated by LIG4 are either insufficient to support transforming genomic rearrangements or are incompatible with cell viability. Mitotic slippage in the absence of cell cycle regulators, including tumor protein p53 (TP53), increases the fusogenic substrate pool and extends the lifespan of genetically unstable cells (Davoli et al 2010;Hayashi et al 2015). The nature of the DNA lesions activating different NHEJ pathways (Rai et al 2010) and the ultimate balance between the resulting long-range inter-chromosomal and short-range intra-chromosomal telomeric fusions significantly impact cellular capacity for evolution and survival.…”

Telomere biology in aging and cancer: early history and perspectives

“…gesting an active pathway inducing the intermediate-state telomere during mitotic arrest. This partially explains a mechanism underlying cell death upon anti-tumor druginduced mitotic arrest (Hayashi et al, 2015). The intermediate-state telomere may thus function as a biological sensor for cellular stresses, such as prolonged mitosis and cellular chronological aging .…”

“…At least in fibroblasts, chromosome end-to-end fusion was shown to trigger mitotic arrest by an unknown mechanism, which leads to mitotic telomere deprotection and cell death during the same mitosis or the following cell cycle (Hayashi et al, 2015). Cell death following mitotic arrest is dominant in telomere crisis of fibroblasts, providing a novel insight about the mechanism of cell death during this catastrophic stage.…”