Short-term molecular consequences of chromosome mis-segregation for genome stability

Abstract

Chromosome instability (CIN) is the most common form of genome instability and is a hallmark of cancer. CIN invariably leads to aneuploidy, a state of karyotype imbalance. Here, we show that aneuploidy can also trigger CIN. We found that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN. This generates a repertoire of genetically diverse cells with structural chromosomal abnormalities that can either continue proliferating or stop dividing. Cycling aneuploid cells display lower karyotype complexity compared to the arrested ones and increased expression of DNA repair signatures. Interestingly, the same signatures are upregulated in highly-proliferative cancer cells, which might enable them to proliferate despite the disadvantage conferred by aneuploidy-induced CIN. Altogether, our study reveals the short-term origins of CIN following aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for aneuploidy occurrence in tumors.

Differential effects of aneuploidy on growth and differentiation in human intestinal stem cells

“…DNA damage, which may result from chromosome mis-segregation or replication stress, has been proposed to lead to p53 activation in aneuploid cells. 9,10,23,26,27 However, in colonoids expressing H2B-mNeon and mCherry-53BP1, DNA damage foci were infrequently observed following chromosome mis-segregation and did not increase following mitosis in the presence of 0.5 µM reversine (Figure 2C). To assess whether replication stress in aneuploid cells could cause DNA damage and lead to p53 activation, we treated colonoids with 0.25 or 0.5 µM reversine for 4 hours, followed by 16 hours in drug-free media to allow cells to progress through S phase.…”

Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

“…For example, a very recent study indicates that aneuploid cells undergo replication stress which results in CIN and in a diverse outcome of karyotypic complexities and cell fates in their progeny. Of note, in this context, aneuploid/CIN cells that are able to sustain a proliferative status are shown to turn up DNA repair pathways (Garribba et al 2023 ). Remarkably, another study has reported cancer-specific epigenetic vulnerabilities in tumor cells with underlying genomic instability that makes them sensitive to targeting the acetyltransferase complex MLS, which leads to exacerbation of under-replicated DNA, CIN, and extreme levels of aneuploidy (Monserrat et al 2021 ).…”

Single-cell DNA replication dynamics in genomically unstable cancers

“…At a more granular level, the relative timing at which different regions of the genome replicate during sythesis (S)-phase of the cell cycle, known as replication timing (RT), is strongly associated with epigenomic features including 3D nuclear organization, chromatin state, and transcription, and cellular phenotype [6][7][8][9][10]. Structural variation and CNAs have been shown to impact epigenomic and chromatin state, and may also impact RT [11][12][13][14]. Additionally, specific genomic alterations confer fitness advantages, producing genetically distinct subclones with unique proliferation rates and thus more rapid progression through the cell cycle.…”

“…First, since early and late RT loci are known to have different DNA damage and repair rates [26][27][28], we investigated the relationship between ancestral RT and the emergence of CNAs. Second, we modeled the relative impact of cell type, mutational signature, and ploidy on RT and the distribution of early vs late S-phase cells because these features have been shown to correlate with replication origin placement, replication stress response, perturbed epigenetic state, and 3D nuclear organization [7,[11][12][13][14][29][30][31]. Third, we leveraged the fact that the inactive chromosome X allele (Xi) replicates very late within S-phase [22,32] to identify recurrent patterns of Xi selection in TNBC and HGSOC tumors.…”