The presence of extra chromosomes leads to genomic instability

Abstract

Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis.

CIN and Aneuploidy: Different Concepts, Different Consequences

“…The effects of CIN have been found to be strongly dependent on the rate and type of chromosome mis-segregation or mitotic defect. [14][15][16][17][18] CIN is often measured in a tissue culture setting, which we, for the purpose of this review, define as in vitro. CIN can be quantified via time-lapse microscopy or immunofluorescence staining of fixed cells in mitosis.…”

“…[14][15][16][17][18] In vitro CIN measurements can also be used to characterize animal models. For instance, some studies make use of mouse embryonic fibroblasts (MEFs) from mouse models of genetically induced CIN to estimate the in vivo rate of CIN.…”

“…[40,41] Indeed, several trisomies, tetrasomies, and a few doubletrisomies were shown to cause further mis-segregation events in both cancer and non-cancer cell lines. [17,18] A trisomy of chromosome 13 in human cells can lead to failing cytokinesis, while a trisomy of chromosome 7 does not, showing that different aneuploid karyotypes can cause different forms of CIN. [17] However, in fully triploid fibroblasts (three copies of each chromosome) the percentage of aneuploid cells increases, but the rate of chromosome mis-segregation (CIN), relative to a euploid control, does not.…”

“…[7,8,18,42] This growth defect is caused by the deregulation of the proteasome, [1,[43][44][45][46] cell metabolism, [47] transcriptome, [41] and the increase in cellular senescence. [42,48] However, not all aneuploidies have the same effect on cells.…”

“…[1] For example 25% of non-cancer mouse cell lines are aneuploid [49] and RPE-1 cells (a human, non-cancer cell line which was initially euploid when harvested) often display clonal gain of chromosome 10q and 12. [18] Gains of chromosomes 12 and 17 have also been reported to be quite common in human pluripotent stem cells (hPSCs), [56] with gain of chromosome 12 in hPSCs to cause a growth benefit. [1] …”