Involvement of Centrosome Amplification in Radiation-Induced Mitotic Catastrophe

Dodson, Helen; Wheatley, Sally P.; Morrison, Ciarán

doi:10.4161/cc.6.3.3834

Cited by 74 publications

(64 citation statements)

References 42 publications

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“…The formation of multinuclear cells and multipolar spindle in cells after DNA damage is the characteristic of cells undergoing mitotic catastrophe (18,35,36). Using time-lapse video microscopy, we aimed to detect the association between DNA-PKcs deficiency and mitotic catastrophe in response to DNA damage.…”

Section: Resultsmentioning

confidence: 99%

Inactivation of DNA-Dependent Protein Kinase Leads to Spindle Disruption and Mitotic Catastrophe with Attenuated Checkpoint Protein 2 Phosphorylation in Response to DNA Damage

Shang

Huang

et al. 2010

Cancer Research

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DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is well known as a critical component involving the nonhomologous end joining pathway of DNA double-strand breaks repair. Here, we showed another important role of DNA-PKcs in stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. Inactivation of DNA-PKcs by small interfering RNA or specific inhibitor NU7026 resulted in an increased outcome of polyploidy after 2-Gy or 4-Gy irradiation. Simultaneously, a high incidence of multinucleated cells and multipolar spindles was detected in DNA-PKcs-deficient cells. Time-lapse video microscopy revealed that depression of DNA-PKcs results in mitotic catastrophe associated with mitotic progression failure in response to DNA damage. Moreover, DNA-PKcs inhibition led to a prolonged G 2 -M arrest and increased the outcome of aberrant spindles and mitotic catastrophe in Ataxia-telangiectasia mutated kinase (ATM)-deficient AT5BIVA cells. We have also revealed the localizations of phosphorylated DNA-PKcs/T2609 at the centrosomes, kinetochores, and midbody during mitosis. We have found that the association of DNA-PKcs and checkpoint kinase 2 (Chk2) is driven by Ku70/80 heterodimer. Inactivation of DNA-PKcs strikingly attenuated the ionizing radiation-induced phosphorylation of Chk2/T68 in both ATMefficient and ATM-deficient cells. Chk2/p-T68 was also shown to localize at the centrosomes and midbody. These results reveal an important role of DNA-PKcs on stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage and provide another prospect for understanding the mechanism coupling DNA repair and the regulation of mitotic progression. Cancer Res; 70(9); 3657-66. ©2010 AACR.

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Section: Resultsmentioning

confidence: 99%

Inactivation of DNA-Dependent Protein Kinase Leads to Spindle Disruption and Mitotic Catastrophe with Attenuated Checkpoint Protein 2 Phosphorylation in Response to DNA Damage

Shang

Huang

et al. 2010

Cancer Research

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“…For live cell imaging, cells were stably transfected with a pmRFP-N1-H2B, which encodes red fluorescent protein (RFP)-tagged histone H2B. 51 Before imaging, cells were cultured in media supplemented with 12.5 mM Hepes (pH 7.5) in poly-D-lysine-coated dishes (MatTek) for 3 h. Time-lapse images were acquired for 3h at 3 min intervals on a DeltaVision integrated microscope system using a PlanApo N60× oil objective (N.A. 1.42) and a WeatherStation environmental chamber at 39.5°C (Precision Control).…”

Section: Methodsmentioning

confidence: 99%

Promoter hijack reveals pericentrin functions in mitosis and the DNA damage response

et al. 2013

Self Cite

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“…i) Recent studies have shown that several DNA repair proteins localize to the centrosome, and defects in these proteins cause several functional aberrations in centrosomes such as centrosome amplification. [40][41][42][43] Also, it has been shown that DNA damage can induce centrosome amplification. [41][42][43] Overexpression of Usp1 in NIH3T3 cells inhibited UV-induced Fancd2-Ub and PCNA-Ub (Fig.…”

Section: Discussionmentioning

confidence: 99%

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

2016

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Defects in the regulation of centrosome duplication lead to tumorigenesis through abnormal cell division and resulting chromosome missegregation. Therefore, maintenance of accurate centrosome number is critical for cell fate. The deubiquitinating enzyme USP1 plays important roles in DNA repair and cell differentiation. Importantly, increased levels of USP1 are detected in certain types of human cancer, but little is known about the significance of USP1 overexpression in cancer development. Here we show that Usp1 plays a novel role in regulating centrosome duplication. The ectopic expression of wild-type Usp1, but not C90S Usp1 (catalytically inactive mutant form), induced centrosome amplification. Conversely, ablation of Usp1 in mouse embryonic fibroblasts (MEFs) showed a significant delay in centrosome duplication. Moreover, Usp1-induced centrosome amplification caused abnormal mitotic spindles, chromosome missegregation and aneuploidy. Interestingly, loss of inhibitor of DNA binding protein 1 (ID1) suppressed Usp1-induced centrosome amplification. Taken together, our results strongly suggest that Usp1 is involved in the regulation of centrosome duplication, at least in part via ID1, and Usp1 may exert its oncogenic activity, partially through inducing centrosome abnormality.

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Involvement of Centrosome Amplification in Radiation-Induced Mitotic Catastrophe

Cited by 74 publications

References 42 publications

Inactivation of DNA-Dependent Protein Kinase Leads to Spindle Disruption and Mitotic Catastrophe with Attenuated Checkpoint Protein 2 Phosphorylation in Response to DNA Damage

Inactivation of DNA-Dependent Protein Kinase Leads to Spindle Disruption and Mitotic Catastrophe with Attenuated Checkpoint Protein 2 Phosphorylation in Response to DNA Damage

Promoter hijack reveals pericentrin functions in mitosis and the DNA damage response

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

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