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

• Published in: Molecular biology of the cell 2020-11, Vol.31 (24), p.2646-2656
• Main Authors: Sala, Roberta, Farrell, K C, Stearns, Tim
• Format: Article
• Language: English
• Subjects: Brief Reports; Cell Cycle - physiology; Cell Cycle Checkpoints - physiology; Cell Cycle Proteins - metabolism; Cell Line; Cell Proliferation - physiology; Centrioles - metabolism; Centrioles - physiology; Centrosome - metabolism; Homeostasis; Humans; Interphase - physiology; Mitosis; Protein Serine-Threonine Kinases - metabolism; Protein Serine-Threonine Kinases - physiology; Retinal Pigment Epithelium - metabolism
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E19-04-0195

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 results 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 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.