The Dynamic Instability of the Aneuploid Genome

Garribba, Lorenza; Santaguida, Stefano

doi:10.3389/fcell.2022.838928

Cited by 18 publications

(13 citation statements)

References 81 publications

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“…For example, a comparison between trisomic and diploid human cells has revealed that aneuploid cells are characterized by increased frequency of lagging chromosomes in anaphase 23,24 . Thus, this evidence points at aneuploidy as an instigator of genome instability 20 . It is plausible that this instability is due to the strong impact of karyotype abnormalities on gene expression and protein homeostasis.…”

Section: Introductionmentioning

confidence: 72%

“…This might be due to the fact that specific aneuploid karyotypes could confer a proliferative advantage, thus fueling tumorigenesis 7,8 and promoting survival under sub-optimal conditions 5,6 . Such an advantage could be explained by the possibility that aneuploidy induces CIN (and, more broadly, genome instability), which might enable a continuous sculpting of the genome, eventually leading to cumulative haploinsufficiency and triplosensitivity 19,20 of genes crucial for sustained proliferation. In agreement with this idea, studies in yeast have demonstrated that gain of a single chromosome leads to defective DNA damage repair 15 .…”

Section: Introductionmentioning

confidence: 99%

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

Feudis

Garribba

Martis

et al. 2022

Preprint

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Genome instability is a hallmark of cancer. The most common form of genome instability is chromosomal instability (CIN), a condition in which cells mis-segregate their chromosomes during cell division. CIN leads to aneuploidy, a state of karyotype imbalance, often found in tumors. Although the causal relationship between CIN and aneuploidy is well established, evidence is limited for a direct involvement of aneuploidy in promoting CIN. Here, we show that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN, eventually accumulating complex karyotypes. Mechanistically, we find that aneuploid cells fire dormant replication origins through a Dbf4-dependent kinase (DDK)-driven mechanism and complete replication of genomic loci through mitotic DNA synthesis (MiDAS). By following the fate of aneuploid cells, we also show that, when they divide, DNA damage can be distributed asymmetrically between daughter cells, and this may partially explain why some aneuploid cells are able to continue proliferating and others stop dividing. We further found that cycling aneuploid cells display lower karyotype complexity compared to arrested ones and increased expression of gene signatures associated to DNA repair. Interestingly, by stratifying aneuploid human cancer cells by their doubling times, we found the same DNA repair signatures to be upregulated in highly-proliferative cancer cells, which might enable them to keep proliferating despite the disadvantage conferred by aneuploidy-induced genome instability. In summary, our study reveals the origins of genome instability following induction of aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for the high occurrence of aneuploidy in tumors.

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Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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

Feudis

Garribba

Martis

et al. 2022

Preprint

Self Cite

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“…Defects in chromosome segregation during mitosis, which not only generate cells with incorrect numbers of chromosomes but also precipitate drastic chromosome rearrangements, are intermediates during the generation of nearly all cancers (Garribba and Santaguida, 2022; Li and Zhu, 2022). Given the hundreds of billions of cells that divide in an adult human every day, monitoring these mitoses to filter out potentially problematic cells poses a significant challenge.…”

Section: Discussionmentioning

confidence: 99%

Control of cell proliferation by memories of mitosis

Meitinger

Davis

Martinez

et al. 2022

Preprint

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Mitotic duration is tightly constrained, with extended mitotic duration being a characteristic of potentially problematic cells prone to chromosome missegregation and genomic instability. We show that memories of mitotic duration are integrated by a p53-based mitotic stopwatch pathway to exert tight control over proliferation. The stopwatch halts proliferation of the products of a single significantly extended mitosis or of successive modestly extended mitoses. Time in mitosis is monitored via mitotic kinase-regulated assembly of stopwatch complexes that are transmitted to daughter cells. The stopwatch is inactivated in p53-mutant cancers, as well as in a significant proportion of p53-wildtype cancers, consistent with classification of stopwatch complex subunits as tumor suppressors. Stopwatch status additionally influences efficacy of anti-mitotic agents currently used or in development for cancer therapy.

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“…Deformation changes in cells’ architectural structures or mechanical properties give rise to internal forces balancing external loads, leading to mechanical stresses. During carcinogenesis, a continuum of mechanical pressures increases, which leads to genome instability in cancer cells, resulting in loss of heterozygosity (LOH), abnormal/multipolar cell division, DNA breaks/rearrangement, micronucleus formation, and DNA copy number variations [ 119 , 120 ]. These genetic events create DNA fragments inside the cells that mimic viral infection.…”

Section: Regulation Of Immune Tme By Mutations In Cytoskeleton-associ...mentioning

confidence: 99%

Alterations of Cytoskeleton Networks in Cell Fate Determination and Cancer Development

et al. 2022

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Cytoskeleton proteins have been long recognized as structural proteins that provide the necessary mechanical architecture for cell development and tissue homeostasis. With the completion of the cancer genome project, scientists were surprised to learn that huge numbers of mutated genes are annotated as cytoskeletal or associated proteins. Although most of these mutations are considered as passenger mutations during cancer development and evolution, some genes show high mutation rates that can even determine clinical outcomes. In addition, (phospho)proteomics study confirms that many cytoskeleton-associated proteins, e.g., β-catenin, PIK3CA, and MB21D2, are important signaling mediators, further suggesting their biofunctional roles in cancer development. With emerging evidence to indicate the involvement of mechanotransduction in stemness formation and cell differentiation, mutations in these key cytoskeleton components may change the physical/mechanical properties of the cells and determine the cell fate during cancer development. In particular, tumor microenvironment remodeling triggered by such alterations has been known to play important roles in autophagy, metabolism, cancer dormancy, and immune evasion. In this review paper, we will highlight the current understanding of how aberrant cytoskeleton networks affect cancer behaviors and cellular functions through mechanotransduction.

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The Dynamic Instability of the Aneuploid Genome

Cited by 18 publications

References 81 publications

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

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

Control of cell proliferation by memories of mitosis

Alterations of Cytoskeleton Networks in Cell Fate Determination and Cancer Development

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