p53 Prohibits Propagation of Chromosome Segregation Errors that Produce Structural Aneuploidies

Abstract

The presence of an abnormal karyotype has been shown to be profoundly detrimental at the cellular and organismal levels but is an overt hallmark of cancer. Aneuploidy can lead to p53 activation and thereby prevents proliferation, but the exact trigger for p53 activation has remained controversial. Here, we have used a system to induce aneuploidy in untransformed human cells to explore how cells deal with different segregation errors. We show that p53 is activated only in a subset of the cells with altered chromosome content. Importantly, we find that at least a subset of whole-chromosome aneuploidies can be propagated in p53-proficient cells, indicating that aneuploidy does not always lead to activation of p53. Finally, we demonstrate that propagation of structural aneuploidies (gain or loss of part of a chromosome) induced by segregation errors is limited to p53-deficient cells.

Putting p53 in Context

“…Accordingly, TP53 mutations are also associated with whole genome doubling events in human tumors (Cancer Genome Atlas Research, 2013). Additional studies suggest that p53-deficient cells are better at tolerating proteomic stress produced by aberrant gene dosage (Tang et al, 2011), yet others suggest that p53-mediated culling of aneuploid cells is more efficient against structural aneuploidy than whole chromosome imbalances, implicating the role of DDR in response to chromosome shearing (Soto et al., 2017). Hence, it appears that the absence of p53 both facilitates the accumulation and permits the survival of aneuploid cells.…”

Cellular Stress Associated with Aneuploidy

“…In fact, in many aneuploid yeast strains with simple or complex chromosome stoichiometry (Pavelka et al, 2010), a propensity for protein aggregation was not evident (our unpublished observations). Studies that involved acute induction of aneuploidy in mammalian cell lines may be complicated by the possible presence of genotoxic or metabolic stress in these cells, which are also known to induce autophagy (Balaburski et al, 2010; Santaguida et al, 2017; Santaguida et al, 2015; Soto et al, 2017; White, 2016; Xiao et al, 2015). Finally, the extent to which an aneuploid genome can tolerate extra protein expression may vary greatly from karyotype to karyotype.…”

“…In addition to increased DNA damage, aneuploid cells experiencing replication stress (including those harboring DNA damage) are also subject to several other fates, such as cell cycle delays, DNA condensation defect, inappropriate mitotic entry, senescence, and even immunological recognition and destruction (Andriani et al, 2016; Blank et al, 2015; Burrell et al, 2013; Lamm et al, 2016; Meena et al, 2015; Santaguida et al, 2017; Soto et al, 2017). Cell cycle delays associated with replication stress may be a cause of the perturbation in cell cycle/proliferative dynamics observed for aneuploid cells in the past (Segal and McCoy, 1974; Stingele et al, 2012; Williams et al, 2008).…”

p53 induces senescence in the unstable progeny of aneuploid cells

“…One such cell-autonomous strategy is centered on the transcription factor and tumor suppressor protein p53, which relocates to the cell nucleus to promote specific transcriptional responses to a variety of stress stimuli [14]. Previous reports have suggested that activation of p53 can be triggered directly via the stress kinase p38 [15] or mediated by DNA damage or accumulation of reactive oxygen species (ROS) following chromosome mis-segregation [16][17][18]. Other data suggest that phosphorylation of histone H3 on mis-segregated chromosomes is sufficient to stabilize p53 independently of key DNA-damaging signaling proteins [19].…”

“…Other data suggest that phosphorylation of histone H3 on mis-segregated chromosomes is sufficient to stabilize p53 independently of key DNA-damaging signaling proteins [19]. However, accumulating evidence indicates that aneuploid cells can escape p53 signaling, and aneuploid cell lines can be established in vitro [11,18,20]. These aberrant aneuploid cells produce pro-inflammatory signals and can thus be actively removed by the host immune system in vivo [20].…”