Growth disadvantage associated with centrosome amplification drives population-level centriole number homeostasis

Abstract

The centriole duplication cycle normally ensures that centriole number is maintained at two centrioles per G1 cell. However, some circumstances can result in an aberrant increase in centriole number—a phenotype that is particularly prevalent in several types of cancer. Following an artificial increase in centriole number without tetraploidization due to transient overexpression of the kinase PLK4, human cells return to a normal centriole number during the proliferation of the population. We examine the mechanisms responsible for this return to normal centriole number at the population level in human retinal pigment epithelial cells. We find that the return to normal centriole number in the population of induced cells cannot be explained by limited duplication of centrioles, instability of extra centrioles, or by grossly asymmetric segregation of extra centrioles in mitosis. However, cells with extra centrioles display heterogenous phenotypes including extended cell cycle arrest, longer interphase durations, and death, which overall result in a proliferative disadvantage relative to normal cells in the population. Although about half of cells with extra centrioles in a population were able to divide, the extent of the disadvantages conferred by other fates is sufficient to account for the observed rate of return to normal centriole number. These results suggest that only under conditions of either positive selection for cells with extra centrioles, continuous generation of such centrioles, or alleviation of the disadvantageous growth phenotypes, would they be maintained in a population.

Patterns of selection against centrosome amplification in human cell lines

“…This model is the continuous-time equivalent of the model proposed by Moran [ 27 ], in the absence of back mutation, and included in the framework of the original quasispecies model [ 28 – 30 ]. As previously mentioned, several lines of evidence suggest that centriole numbers in proliferating cell populations follow a stable equilibrium distribution when unperturbed [ 17 – 20 , 31 ]. We propose the following expression that describes a fully polymorphic equilibrium distribution, i.e.…”

“…Whereas after correct centriole duplication, each daughter cell inherits a single centriolar pair, it is still unclear how extra centrioles are distributed. However, while this manuscript was in review, Sala et al reported that the degree of asymmetry in centriole segregation increases with the number of extra centrioles in RPE-1 cells transiently overexpressing Plk4 [ 31 ]. Since most cells with centrosome amplification in the samples we have analysed contain only a few extra centrioles, it can be expected that centriole segregation is predominantly symmetrical.…”

Centrosome instability: when good centrosomes go bad

“…Fascinatingly, when certain cancer cells lines that stably maintain an abnormally high number of centrosomes are exposed to a centrinone treatment and washout regimen, the population does not correct to a normal centrosome number. Instead, the dividing population eventually returns to their abnormal basal level of amplification and appear the same as the untreated control cells [ 123 , 194 ]. At present, it is a mystery how cells can establish and maintain memory of abnormal centrosome copy number [ 194 ].…”

Generation and Fates of Supernumerary Centrioles in Dividing Cells

“…2; Chiba et al, 2000). For example, cells with supernumerary centrioles generated by PLK4 overexpression go through longer durations of both interphase and mitosis, which overall imparts growth disadvantages in comparison to cells with normal centriole numbers (Sala, et al, 2020). Tetraploid cells that lose extra centrosomes over time may be another example of clonal elimination of cells with extra centrioles (Krzywicka-Racka and Sluder, 2011;Mikeladze-Dvali et al, 2012).…”

“…The number of centrioles doubles after cells pass through the G1/S transition phase. However, supernumerary centrioles are not always doubled, suggesting that a fraction of centrioles may be inactive in centriole assembly (Sala et al, 2020). Heterogeneity in supernumerary centrioles has been reported in TP53;PCNT;CEP215 triple knockout cells (Jung and Rhee, 2021).…”