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Highlights
Short dysfunctional telomeres are subjected to fusion with loci across the genome and this leads to the formation of dicentric chromosomes.
Breakage of dicentric chromosomes during cell division leads to simple large-scale deletions and insertions, but complex chromothriptic events can also arise.
A single dysfunctional telomere can initiate a cascade of events that leads to chromothripsis.
It appears that multiple mechanisms underpin chromothripsis-like events, involving micronuclei-dependent and -independent routes and utilizing non-homologous end-joining or replicative repair pathways.
The mutational profile of telomere-driven chromothripsis is consistent with replicative repair processes.
When cells progress to malignancy, they must overcome a final telomere-mediated proliferative lifespan barrier called replicative crisis. Crisis is characterized by extensive telomere fusion that drives widespread genomic instability, mitotic arrest, hyperactivation of autophagy, and cell death. Recently, it has become apparent that that the resolution of dicentric chromosomes, which arise from telomere fusions during crisis, can initiate a sequence of events that leads to chromothripsis, a form of extreme genomic catastrophe. Chromothripsis is characterized by localized genomic regions containing tens to thousands of rearrangements and it is becoming increasingly apparent that chromothripsis occurs widely across tumor types and has a clinical impact. Here we discuss how telomere dysfunction can initiate genomic complexity and the emerging mechanisms of chromothripsis.
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