Examining the link between chromosomal instability and aneuploidy in human cells

Thompson, Sarah L.; Compton, Duane A.

doi:10.1083/jcb.200712029

Cited by 462 publications

(621 citation statements)

References 28 publications

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“…Reportedly, recruitment of PP1 to outer KTs is negatively regulated by Aurora-B-mediated phosphorylation of KNL1 and, accordingly, their physical separation on chromosome biorientation facilitates KT localization of PP1 (refs 18,28-30). On the basis of these observations, we speculated that uncoupling KT localization of PP1 from chromosome biorientation should 33 , transient Eg5 inhibition causes a drastic increase in the incidence of erroneous chromosome segregation events allowing us to monitor the fidelity of sister chromatid segregation under stringent conditions. Importantly, Kif18A-RNAi cells expressing either non-phosphorylatable (2A), GFP-Kif18A (PP1D) deficient in PP1 dephosphorylation or the GFP-Kif18A double mutant (PP1D þ 2A) had significantly more defects in chromosome segregation than identically treated GFP-Kif18A WT -expressing cells.…”

Section: Resultsmentioning

confidence: 99%

Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

et al. 2014

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Section: Resultsmentioning

confidence: 99%

Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

et al. 2014

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“…Chromosome rearrangements generate gene mutations, and, conversely, gene mutations are required to allow maintenance of chromosomal instability and aneuploidy (17). Therefore, we tested gene mutation frequencies at the hypoxanthine-guanine phosphoribosyltransferase (hprt) and thymidine kinase (tk) loci after infection of CHO or HCT-116 cells (Table 1).…”

Section: Increased Gene Mutation Frequency and Anchorage-independentmentioning

confidence: 99%

Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells

Cuevas-Ramos

Petit

Marcq

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

714

618

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Escherichia coli is a normal inhabitant of the human gut. However, E. coli strains of phylogenetic group B2 harbor a genomic island called "pks" that codes for the production of a polyketide-peptide genotoxin, Colibactin. Here we report that in vivo infection with E. coli harboring the pks island, but not with a pks isogenic mutant, induced the formation of phosphorylated H2AX foci in mouse enterocytes. We show that a single, short exposure of cultured mammalian epithelial cells to live pks + E. coli at low infectious doses induced a transient DNA damage response followed by cell division with signs of incomplete DNA repair, leading to anaphase bridges and chromosome aberrations. Micronuclei, aneuploidy, ring chromosomes, and anaphase bridges persisted in dividing cells up to 21 d after infection, indicating occurrence of breakage-fusion-bridge cycles and chromosomal instability. Exposed cells exhibited a significant increase in gene mutation frequency and anchorage-independent colony formation, demonstrating the infection mutagenic and transforming potential. Therefore, colon colonization with these E. coli strains harboring the pks island could contribute to the development of sporadic colorectal cancer.T he dense bacterial consortium, called "microbiota," that inhabits the intestinal tract is recognized increasingly as playing a major role in human health and disease. The microbiota generally influences the host in a beneficial fashion by shaping gastrointestinal and immune functions, exerting protection against pathogens, and contributing to metabolic pathways (1). Escherichia coli is a consistent member of the human intestinal microbiota, colonizing the intestine within a few days after birth and persisting throughout the life of the host. The E. coli strain population can be categorized in at least four major phylogenetic groups (A, B1, B2, and D), each group being more specifically associated with certain ecological niches. E. coli strains belonging to group B2 are recovered from the environment less frequently but can persist longer in the colon than other groups and represent 30-50% of strains isolated from the feces of healthy humans living in high-income countries (2, 3). We recently discovered that up to 34% of commensal E. coli strains of the phylogenetic group B2 carry a conserved genomic island named "pks island" (4-6). This gene cluster codes for nonribosomal peptide synthetases (NRPS) and polyketide synthetases (PKS) that allow production of a putative hybrid peptide-polyketide genotoxin, Colibactin. In vitro infection with these strains induces DNA double-strand breaks (DSBs) in cultivated human cells, but the pks island was not proved to cause DNA damage in vivo (4).In this study, we wished to explore whether those bacteria were able to induce genetic damage in vivo on the colonic mucosa and to characterize the consequences of this damage on mammalian cells in relation with the number of infecting bacteria. We report that pks + E. coli induced DSBs in vivo. In addition, infection of various ma...

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“…Merotelic attachments appear to be an important cause of aneuploidy in CIN, are common in metaphase and early anaphase, and are not recognized efficiently by the spindle checkpoint. 35,36 A tensionbased mechanism for the correction of merotelic attachments has therefore been proposed. 37 In a single merotelic attachment, approximately ten microtubules are projected to one pole and five microtubules to the opposite pole.…”

Section: The Spindle As a Break-generating Devicementioning

confidence: 99%

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Martı́nez-A

Wely

2010

Cell Cycle

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G enetic instability is a hallmark of cancer. Most tumors show complex patterns of translocations, amplifications and deletions, which have occupied scientists for decades. A specific problem arises in carcinomas with a genetic defect termed chromosomal instability; these solid tumors undergo gains and losses of entire chromosomes, as well as segmental defects caused by chromosome breaks. To date, the apparent inconsistency between intact and broken chromosomes has precluded identification of an underlying mechanism. The recent identification of centromeric breaks alongside aneuploidy in cells with spindle defects indicates that a single mechanism could account for all genetic alterations characteristic of chromosomal instability. Since a poorly controlled spindle can cause merotelic attachments, kinetochore distortion and subsequent chromosome breakage, spindle defects can generate the sticky ends necessary to start a breakagefusion-bridge cycle. The characteristic breakpoint of spindle-generated damage, adjacent to the centromere, also explains the losses and gains of whole chromosome arms, which are especially prominent in low-grade tumors. The recent data indicate that spindle defects are an early event in tumor formation, and an important initiator of carcinogenesis.

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Examining the link between chromosomal instability and aneuploidy in human cells

Cited by 462 publications

References 28 publications

Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

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