Too much to handle — how gaining chromosomes destabilizes the genome

Passerini, Verena; Storchová, Zuzana

doi:10.1080/15384101.2016.1231285

Cited by 8 publications

(5 citation statements)

References 80 publications

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“…CIN is a hallmark of cancer cells 1 , 11 – 13 , and while various mechanisms can lead to chromosome miss-segregation 5 , 14 – 19 , SAC alleviation is commonly used as a tool to provoke CIN in model systems. While SAC genes are rarely mutated 20 , SAC function has been found to be impaired in various human cancers 20 , 21 .…”

Section: Introductionmentioning

confidence: 99%

Acute systemic loss of Mad2 leads to intestinal atrophy in adult mice

Schukken

Zhu

Bakker

et al. 2021

Sci Rep

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Chromosomal instability (CIN) is a hallmark of cancer, leading to aneuploid cells. To study the role that CIN plays in tumor evolution, several mouse models have been engineered over the last 2 decades. These models have unequivocally shown that systemic high-grade CIN is embryonic lethal. We and others have previously shown that embryonic lethality can be circumvented by provoking CIN in a tissue-specific fashion. In this study, we provoke systemic high-grade CIN in adult mice as an alternative to circumvent embryonic lethality. For this, we disrupt the spindle assembly checkpoint (SAC) by alleviating Mad2 or truncating Mps1, both essential genes for SAC functioning, with or without p53 inactivation. We find that disruption of the SAC leads to rapid villous atrophy, atypia and apoptosis of the epithelia of the jejunum and ileum, substantial weight loss, and death within 2–3 weeks after the start of the CIN insult. Despite this severe intestinal phenotype, most other tissues are unaffected, except for minor abnormalities in spleen, presumably due to the lower proliferation rate in these tissues. We conclude that high-grade CIN in vivo in adult mice is most toxic to the high cell turnover intestinal epithelia.

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Section: Introductionmentioning

confidence: 99%

Acute systemic loss of Mad2 leads to intestinal atrophy in adult mice

Schukken

Zhu

Bakker

et al. 2021

Sci Rep

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“…Therefore, we tested the hypothesis that QnrB can cause DNA replication stress without the involvement of gyrase. DNA replication stress can affect DNA replication and the segregation of chromosomes (Passerini and Storchova, ; Zhang et al , ), thus influencing the DNA content of cells (Taylor et al , ). Consequently, we examined the genomic DNA and plasmid contents of two E. coli strains expressing (pQE‐ qnrB /BW25113) or lacking (pQE/BW25113) QnrB.…”

Section: Resultsmentioning

confidence: 99%

The plasmid‐borne quinolone resistance protein QnrB, a novel DnaA‐binding protein, increases the bacterial mutation rate by triggering DNA replication stress

Zhang

Zhou

et al. 2019

Molecular Microbiology

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Summary Bacterial antibiotic resistance, a global health threat, is caused by plasmid transfer or genetic mutations. Quinolones are important antibiotics, partially because they are fully synthetic and resistance genes are unlikely to exist in nature; nonetheless, quinolone resistance proteins have been identified. The mechanism by which plasmid‐borne quinolone resistance proteins promotes the selection of quinolone‐resistant mutants is unclear. Here, we show that QnrB increases the bacterial mutation rate. Transcriptomic and genome sequencing analyses showed that QnrB promoted gene abundance near the origin of replication (oriC). In addition, the QnrB expression level correlated with the replication origin to terminus (oriC/ter) ratio, indicating QnrB‐induced DNA replication stress. Our results also show that QnrB is a DnaA‐binding protein that may act as an activator of DNA replication initiation. Interaction of QnrB with DnaA promoted the formation of the DnaA‐oriC open complex, which leads to DNA replication over‐initiation. Our data indicate that plasmid‐borne QnrB increases bacterial mutation rates and that genetic changes can alleviate the fitness cost imposed by transmitted plasmids. Derivative mutations may impair antibiotic efficacy and threaten the value of antibiotic treatments. Enhanced understanding of how bacteria adapt to the antibiotic environment will lead to new therapeutic strategies for antibiotic‐resistant infections.

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“…Aneuploidy has also been associated with the downregulation of replication factors, in particular the subunits of the replicative helicase MCM2-7 [31,98]. The resulting replication stress can lead to extra-chromosomal instability, such as an increase in the frequency of anaphase bridges as observed in aneuploid HCT116 and RPE1 cells.…”

Section: Potential Aneuploidy-targeting Therapeutic Strategiesmentioning

confidence: 99%

Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer

2020

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Aneuploidy, an irregular number of chromosomes in cells, is a hallmark feature of cancer. Aneuploidy results from chromosomal instability (CIN) and occurs in almost 90% of all tumours. While many cancers display an ongoing CIN phenotype, cells can also be aneuploid without displaying CIN. CIN drives tumour evolution as ongoing chromosomal missegregation will yield a progeny of cells with variable aneuploid karyotypes. The resulting aneuploidy is initially toxic to cells because it leads to proteotoxic and metabolic stress, cell cycle arrest, cell death, immune cell activation and further genomic instability. In order to overcome these aneuploidy-imposed stresses and adopt a malignant fate, aneuploid cancer cells must develop aneuploidy-tolerating mechanisms to cope with CIN. Aneuploidy-coping mechanisms can thus be considered as promising therapeutic targets. However, before such therapies can make it into the clinic, we first need to better understand the molecular mechanisms that are activated upon aneuploidization and the coping mechanisms that are selected for in aneuploid cancer cells. In this review, we discuss the key biological responses to aneuploidization, some of the recently uncovered aneuploidy-coping mechanisms and some strategies to exploit these in cancer therapy.

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Too much to handle — how gaining chromosomes destabilizes the genome

Cited by 8 publications

References 80 publications

Acute systemic loss of Mad2 leads to intestinal atrophy in adult mice

Acute systemic loss of Mad2 leads to intestinal atrophy in adult mice

The plasmid‐borne quinolone resistance protein QnrB, a novel DnaA‐binding protein, increases the bacterial mutation rate by triggering DNA replication stress

Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer

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