A New Mode of Mitotic Surveillance

Lambrus, Bramwell G.; Holland, Andrew J.

doi:10.1016/j.tcb.2017.01.004

Cited by 66 publications

(66 citation statements)

References 32 publications

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“…This observation led to the interesting proposal that the cells somehow “know” how many chromosomes they have and that a chromosome number that deviates from the euploid karyotype triggers a p53 response. However chromosome mis-segregation brought about by interfering with spindle function results in a mitotic delay, which when it exceeds 100 minutes causes p53 activation in the subsequent G1 phase irrespective of whether or not chromosome mis-segregation occurred (Uetake and Sluder, 2010) and requires the DNA damage binding protein 53BP1 and the deubiquitinating enzyme USP28 (Lambrus and Holland, 2017). To examine the effects of chromosome mis-segregation on cell cycle progression without this complication, we used methods to interfere with chromosome segregation that accelerated rather than delayed mitosis.…”

Section: Discussionmentioning

confidence: 99%

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

et al. 2017

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SUMMARY Aneuploidy, a state of karyotype imbalance, is a hallmark of cancer. Changes in chromosome copy number have been proposed to drive disease by modulating the dosage of cancer driver genes and by promoting cancer genome evolution. Given the potential of cells with abnormal karyotypes to become cancerous, do pathways exist that limit the prevalence of such cells? By investigating the immediate consequences of aneuploidy on cell physiology, we identified mechanisms that eliminate aneuploid cells. We find that chromosome mis-segregation leads to further genomic instability that ultimately causes cell cycle arrest. We further show that cells with complex karyotypes exhibit features of senescence and produce pro-inflammatory signals that promote their clearance by the immune system. We propose that cells with abnormal karyotypes generate a signal for their own elimination that may serve as a means for cancer cell immunosurveillance.

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Section: Discussionmentioning

confidence: 99%

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

et al. 2017

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“…Nevertheless, there is evidence to suggest that activation of the mitotic surveillance pathway could underlie the growth defects observed in primary microcephaly (see below). Future work will be required to elucidate cell and tissue specific differences in signaling though the mitotic surveillance pathway as well as the impact of activation of this pathway in normal physiology and disease 146 .…”

Section: Sensing Centriole Numbermentioning

confidence: 99%

Once and only once: mechanisms of centriole duplication and their deregulation in disease

Nigg

Holland

2018

Nat Rev Mol Cell Biol

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424

546

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Centrioles are conserved microtubule-based organelles that form the core of the centrosome and act as templates for the formation of cilia and flagella. Centrioles have important roles in most microtubule related processes, including motility, cell division and cell signaling. To coordinate these diverse cellular processes, centriole number must be tightly controlled. In cycling cells, one new centriole is formed next to each preexisting centriole in every cell cycle. Advances in imaging, proteomics, structural biology and genome editing have revealed new insights into centriole biogenesis, how centriole numbers are controlled and how alterations in these structures contribute to diseases such as cancer and neurodevelopmental disorders. Moreover, recent work has uncovered the existence of surveillance pathways that limit proliferation of cells with numerical centriole aberrations. Here we discuss recent progress in this field with a focus on signaling pathways and molecular mechanisms.

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“…Recent genome-wide screens have identified a p53-dependent pathway, including the p53-binding protein 53BP1, the deubiquitinase USP38, and the CDK inhibitor p21, that imposes a proliferation arrest on centrosome-deficient cells (Fong et al 2016;Lambrus et al 2016;Meitinger et al 2016). Most likely, this newly discovered pathway detects the extended mitotic duration that is caused by the absence of centrosomes, leading to its designation as "mitotic surveillance pathway" (Lambrus and Holland 2017). In future, it will be interesting to elucidate the exact contributions of this pathway to normal physiology and disease.…”

Section: The Centrosome Duplication Cycle and Its Aberrationsmentioning

confidence: 99%

Impact of Centrosome Aberrations on Chromosome Segregation and Tissue Architecture in Cancer

Nigg

Schnerch

Ganier

2017

Cold Spring Harb Symp Quant Biol

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Centrosomes determine the disposition of microtubule networks and thereby contribute to regulate cell shape, polarity, and motility, as well as chromosome segregation during cell division. Additionally, centrioles, the core components of centrosomes, are required for the formation of cilia and flagella. Mutations in genes coding for centrosomal and centriolar proteins are responsible for several human diseases, foremost ciliopathies and developmental disorders resulting in small brains ( primary microcephaly) or small body size (dwarfism). Moreover, a long-standing postulate implicates numerical and/or structural centrosome aberrations in the etiology of cancer. In this review, we will discuss recent work on the role of centrosome aberrations in the promotion of genome instability and the disruption of tissue architecture, two hallmarks of human cancers. We will emphasize recent studies on the impact of centrosome aberrations on the polarity of epithelial cells cultured in three-dimensional spheroid models. Collectively, the results from these in vitro systems suggest that different types of centrosome aberrations can promote invasive behavior through different pathways. Particularly exciting is recent evidence indicating that centrosome aberrations may trigger the dissemination of potentially metastatic cells through a non-cell-autonomous mechanism.

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A New Mode of Mitotic Surveillance

Cited by 66 publications

References 32 publications

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

Once and only once: mechanisms of centriole duplication and their deregulation in disease

Impact of Centrosome Aberrations on Chromosome Segregation and Tissue Architecture in Cancer

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