Diverse system stresses: common mechanisms of chromosome fragmentation

Abstract

Chromosome fragmentation (C-Frag) is a newly identified MCD (mitotic cell death), distinct from apoptosis and MC (mitotic catastrophe). As different molecular mechanisms can induce C-Frag, we hypothesize that the general mechanism of its induction is a system response to cellular stress. A clear link between C-Frag and diverse system stresses generated from an array of molecular mechanisms is shown. Centrosome amplification, which is also linked to diverse mechanisms of stress, is shown to occur in association with C-Frag. This led to a new model showing that diverse stresses induce common, MCD. Specifically, different cellular stresses target the integral chromosomal machinery, leading to system instability and triggering of MCD by C-Frag. This model of stress-induced cell death is also applicable to other types of cell death. The current study solves the previously confusing relationship between the diverse molecular mechanisms of chromosome pulverization, suggesting that incomplete C-Frag could serve as the initial event responsible for forms of genome chaos including chromothripsis. In addition, multiple cell death types are shown to coexist with C-Frag and it is more dominant than apoptosis at lower drug concentrations. Together, this study suggests that cell death is a diverse group of highly heterogeneous events that are linked to stress-induced system instability and evolutionary potential.

Genome chaos: Survival strategy during crisis

“…C-Frag is a recently characterized form of mitotic cell death that results in shattered-like chromosomal morphology. 20,21,25,26 C-Frag is induced by diverse stresses such as drug treatment or gene mutation and somatic evolution. 26 C-Frag is hypothesized to be a prerequisite for structural genome chaos, as degraded chromosome fragments could be randomly rejoined to form chaotic genomes.…”

Behavior of replication origins in Eukaryota – spatio-temporal dynamics of licensing and firing

“…19 Such alterations of the genetic material raise the probability of somatic evolution. 20 However, the massive DNA replication missbehavior can lead to genome chaos, genome instability and -in this context -can be perceived as relevant to cancer biology.…”

Genome constraint through sexual reproduction: application of 4D-Genomics in reproductive biology

“…Culture conditions for in vitro fertilization represent such an example. Our group recently characterized chromosome fragmentation (C-frag), a form of mitotic cell death distinct from apoptosis, mitotic catastrophe, and premature chromosome condensation (PCC) [Stevens et al 2007;Stevens et al 2010;Stevens et al 2011]. This type of cell death occurs during metaphase where condensed chromosomes are progressively degraded.…”