Abstract
Aneuploidy causes birth defects and miscarriages, occurs in nearly all cancers and is a hallmark of aging. Individual aneuploid cells can be eliminated from developing tissues by unknown mechanisms. Cells with ribosomal protein (Rp) gene mutations are also eliminated, by cell competition with normal cells. Because Rp genes are spread across the genome, their copy number is a potential marker for aneuploidy. We found that elimination of imaginal disc cells with irradiation-induced genome damage often required cell competition genes. Segmentally aneuploid cells derived from targeted chromosome excisions were eliminated by the RpS12-Xrp1 cell competition pathway if they differed from neighboring cells in Rp gene dose, whereas cells with normal doses of the Rp and eIF2γ genes survived and differentiated adult tissues. Thus, cell competition, triggered by differences in Rp gene dose between cells, is a significant mechanism for the elimination of aneuploid somatic cells, likely to contribute to preventing cancer.
Highlights
IntroductionAneuploidy (gain or loss of whole chromosomes resulting in an abnormal karyotype) is a hallmark of spontaneous abortions and birth defects and observed in virtually every human tumor (Hassold and Hunt, 2001; Hanahan and Weinberg, 2011; Lopez-Otın et al, 2013)
Aneuploidy is a hallmark of spontaneous abortions and birth defects and observed in virtually every human tumor (Hassold and Hunt, 2001; Hanahan and Weinberg, 2011; Lopez-Otın et al, 2013)
N = 6 for each genotype. (I) Cell death 24 hr after irradiation (4000 Rad). (J) Comparable levels of cell death in rpS12G97D mutants. (K) cell death appears reduced in p53 mutant wing discs 24 hr after irradiation compared to the wild type control (4000 Rad), this p53-independent cell death is substantially increased compared to 4 hr after irradiation. (L) p53-independent cell death is reduced in the rpS12G97D p53- double mutant compared to the p53- mutant. (M) Cell death quantification in p53 and rpS12G97D p53- wing discs, and in wing discs from rpS12G97D p53- larvae carrying genomic transgenes encoding either wild type rpS12 or rpS12G97D
Summary
Aneuploidy (gain or loss of whole chromosomes resulting in an abnormal karyotype) is a hallmark of spontaneous abortions and birth defects and observed in virtually every human tumor (Hassold and Hunt, 2001; Hanahan and Weinberg, 2011; Lopez-Otın et al, 2013). It was suggested over 100 years ago that aneuploidy contributes to cancer development (Boveri, 1914). Studies of yeast carrying extra chromosomes reveal a stress response in these cells, thought to result from the cumulative mismatch in levels of many proteins that interact in the cell, which inhibits growth (Torres et al, 2007; Zhu et al, 2018; Terhorst et al, 2020)
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