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Interphase cytofission maintains genomic integrity of human cells after failed cytokinesis.

ABSTRACT: In cell division, cytokinesis is tightly coupled with mitosis to maintain genomic integrity. Failed cytokinesis in humans can result in tetraploid cells that can become aneuploid and promote cancer. However, the likelihood of aneuploidy and cancer after a failed cytokinesis event is unknown. Here we evaluated cell fate after failed cytokinesis. We interrupted cytokinesis by brief chemical treatments in cell populations of human epithelial lines. Surprisingly, up to 50% of the resulting binucleate cells generated colonies. In RPE1 cells, 90% of colonies obtained from binucleate founders had a karyotype that matched the parental cell type. Time-lapse videomicroscopy demonstrated that binucleate cells are delayed in the first growth phase of the cell cycle (G1) and undergo interphase cellular fission (cytofission) that distributes nuclei into separate daughters. The fission is not compatible with delayed cytokinesis because events occur in the absence of polymerized microtubules and without canonical components of the cytokinetic machinery. However, the cytofission can be interrupted by inhibiting function of actin or myosin II. Fission events occur in both two- and three-dimensional culture. Our data demonstrate that cytofission can preserve genomic integrity after failed cytokinesis. Thus, traction-mediated cytofission, originally observed in Dictyostelium, is relevant to human biology--where it seems to be an evolutionarily conserved mechanism that can preserve genomic integrity.

SUBMITTER: Choudhary A

PROVIDER: S-EPMC3740861 | biostudies-other | 2013 Aug

REPOSITORIES: biostudies-other

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Interphase cytofission maintains genomic integrity of human cells after failed cytokinesis.

Choudhary Alka A Lera Robert F RF Martowicz Melissa L ML Oxendine Kim K Laffin Jennifer J JJ Weaver Beth A BA Burkard Mark E ME

Proceedings of the National Academy of Sciences of the United States of America 20130722 32

In cell division, cytokinesis is tightly coupled with mitosis to maintain genomic integrity. Failed cytokinesis in humans can result in tetraploid cells that can become aneuploid and promote cancer. However, the likelihood of aneuploidy and cancer after a failed cytokinesis event is unknown. Here we evaluated cell fate after failed cytokinesis. We interrupted cytokinesis by brief chemical treatments in cell populations of human epithelial lines. Surprisingly, up to 50% of the resulting binucleat ...[more]

PMID: 23878225

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Project description:Beta genus human papillomaviruses (?-HPVs) cause cutaneous squamous cell carcinomas (cSCCs) in a subset of immunocompromised patients. However, ?-HPVs are not necessary for tumor maintenance in the general population. Instead, they may destabilize the genome in the early stages of cancer development. Supporting this idea, ?-HPV's 8E6 protein attenuates p53 accumulation after failed cytokinesis. This paper offers mechanistic insight into how ?-HPV E6 causes this change in cell signaling. An in silico screen and characterization of HCT 116 cells lacking p300 suggested that the histone acetyltransferase is a negative regulator of Hippo pathway (HP) gene expression. HP activation restricts growth in response to stimuli, including failed cytokinesis. Loss of p300 resulted in increased HP gene expression, including proproliferative genes associated with HP inactivation. ?-HPV 8E6 expression recapitulates some of these phenotypes. We used a chemical inhibitor of cytokinesis (dihydrocytochalasin B [H2CB]) to induce failed cytokinesis. This system allowed us to show that ?-HPV 8E6 reduced activation of large tumor suppressor kinase (LATS), an HP kinase. LATS is required for p53 accumulation following failed cytokinesis. These phenotypes were dependent on ?-HPV 8E6 destabilizing p300 and did not completely attenuate the HP. It did not alter H2CB-induced nuclear exclusion of the transcription factor YAP. ?-HPV 8E6 also did not decrease HP activation in cells grown to a high density. Although our group and others have previously described inhibition of DNA repair, to the best of our knowledge, this marks the first time that a ?-HPV E6 protein has been shown to hinder HP signaling.IMPORTANCE ?-HPVs contribute to cSCC development in immunocompromised populations. However, it is unclear if these common cutaneous viruses are tumorigenic in the general population. Thus, a more thorough investigation of ?-HPV biology is warranted. If ?-HPV infections do promote cSCCs, they are hypothesized to destabilize the cellular genome. In vitro data support this idea by demonstrating the ability of the ?-HPV E6 protein to disrupt DNA repair signaling events following UV exposure. We show that ?-HPV E6 more broadly impairs cellular signaling, indicating that the viral protein dysregulates the HP. The HP protects genome fidelity by regulating cell growth and apoptosis in response to a myriad of deleterious stimuli, including failed cytokinesis. After failed cytokinesis, ?-HPV 8E6 attenuates phosphorylation of the HP kinase (LATS). This decreases some, but not all, HP signaling events. Notably, ?-HPV 8E6 does not limit senescence associated with failed cytokinesis.

Dataset Information

Interphase cytofission maintains genomic integrity of human cells after failed cytokinesis.

Publications

Interphase cytofission maintains genomic integrity of human cells after failed cytokinesis.

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