Chromosome Segregation Errors as a Cause of DNA Damage and Structural Chromosome Aberrations

Janssen, Aniek; Burg, Marja van der; Szuhai, Károly; Kops, Geert J. P. L.; Medema, René H.

doi:10.1126/science.1210214

Cited by 520 publications

(535 citation statements)

References 27 publications

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“…Recent work in cultured human cells suggests that collisions between the ingressing cleavage furrow and segregating chromosomes can elicit DNA damage and chromosomal aberrations, such as translocations (Janssen et al 2011). This finding underscores the importance of spatiotemporal coordination of chromosome segregation and cytokinesis.…”

Section: Animal Cell Cytokinesismentioning

confidence: 67%

Cytokinesis in Animal Cells

D’Avino

Giansanti

Petronczki

2015

Cold Spring Harb Perspect Biol

176

218

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Section: Animal Cell Cytokinesismentioning

confidence: 67%

Cytokinesis in Animal Cells

D’Avino

Giansanti

Petronczki

2015

Cold Spring Harb Perspect Biol

176

218

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“…Our data confirms and further refines this model, because it shows that P53 is a gatekeeper that prevents acquisition of additional mutations in vivo, and, therefore, early loss P53 is favorable for the progression of CRC. Loss of P53 function allows cells to keep on proliferating, while rendering them sensitive for further accumulation of genetic alternations because of the emergence of CIN (7,11). Indeed, whole genome sequencing revealed different copy number profiles in P53-deficient organoids, derived primary tumor and corresponding spontaneous liver metastasis (SI Appendix, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the observation that cell growth depends on the deletion of P53 has consequences for the order of occurrence of mutations during the adenoma-carcinoma sequence. We and others (7,11) have demonstrated that loss of P53 function in intestinal stem cells induces chromosome instability (CIN). Because CIN can only lead to genetic alterations when cells divide (7,10), our data indicates that P53 is a gatekeeper that prevents acquisition of additional mutations.…”

Section: Significancementioning

confidence: 99%

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

Fumagalli

Drost

Suijkerbuijk

et al. 2017

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

204

188

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In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of defined mutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-β signaling pathways facilitates efficient tumor growth, migration, and metastatic colonization. We show that reconstitution of specific niche signals can restore metastatic growth potential of tumor cells lacking one of the oncogenic mutations. Our findings imply that the ability to metastasize-i.e., to colonize distant sites-is the direct consequence of the loss of dependency on specific niche signals.colorectal cancer | adenoma-carcinoma sequence | organoids | metastasis | niche independence

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“…4B). Accumulation of dsDNA breaks is a consequence of aberrant chromosome segregation (25) and offers a robust and enduring "mark" of such anomalies. We analyzed livers from BrdU-infused GR +/+ and GR +/− mice and found evidence of more dsDNA breaks (γ-H2AX staining) in BrdUtreated GR +/+ animals compared with the GR +/− animals (26).…”

Section: Significancementioning

confidence: 99%

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Matthews

Berry

Morgan

et al. 2015

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

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The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GR expression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene.glucocorticoid receptor | mitosis | aneuploidy | DNA damage | cancer G lucocorticoids (Gcs) act through the glucocorticoid receptor (GR), a member of the nuclear hormone receptor superfamily, and a ligand-activated transcription factor (1-4). The GR is ubiquitously expressed and regulates energy metabolism, immunity, and cell fate decisions. The quiescent GR resides in the cytoplasm in a complex with heat shock proteins and immunophilins, attached to the microtubule architecture of the cell in a heat shock protein 90-dependent manner (5). Ligand binding drives GR transformation, involving N-terminal phosphorylation on S203 and S211 and rapid translocation to the nucleus requiring attachment to dynein by heat shock protein 90, immunophilins, and dynamitin (6). Once in the nucleus, GR binds directly to DNA to regulate transcription, or tethers to other DNA-bound transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP1), to regulate their function (7-10).In mitosis, GR is phosphorylated on both S203 and S211, but in a ligand-independent manner (11), and more comprehensive phosphoproteomic analyses identify the presence of multiple N-terminal GR phosphoforms in purified mitotic spindle fractions (12). Although altered GR function in mitosis has been shown (11, 13, 14), the kinases responsible and cellular consequences have not been defined. The role of G...

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Chromosome Segregation Errors as a Cause of DNA Damage and Structural Chromosome Aberrations

Cited by 520 publications

References 27 publications

Cytokinesis in Animal Cells

Cytokinesis in Animal Cells

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

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