Cell Cycle Synchronization at the G<sub>2</sub>/M Phase Border by Reversible Inhibition of CDK1

Vassilev, Lyubomir T.

doi:10.4161/cc.5.22.3463

Cited by 158 publications

(124 citation statements)

References 13 publications

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“…Addition of RO-3306, a specific inhibitor of Cdk1, impaired the mobility shift of 53BP1 suggesting that 53BP1 is phosphorylated by Cdk1 during mitosis. 27,28 In contrast, treatment with SB202190, a selective inhibitor of mitogen-activated protein kinase p38 a (hereafter reported as p38a) did not significantly change the mobility of mitotic 53BP1. This data suggest that the majority of 53BP1 phosphorylation during mitosis depends on Cdk1 activity, although we cannot exclude some contribution of p38a on phosphorylation of 53BP1.…”

Section: Bp1 Is Phosphorylated By Cdk1 and Plk1 In Mitosismentioning

confidence: 91%

Polo-like kinase 1 inhibits DNA damage response during mitosis

et al. 2015

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Abbreviations: 53BP1, p53 binding protein 1; ATM, ataxia telangiectasia mutated kinase; BRCA1, breast cancer type 1 susceptibility protein; Cdk, cyclin dependent kinase; DDR, DNA damage response; Plk1, Polo-like kinase 1; H2AX, histone variant H2AX; IR -ionizing radiation; MDC1, mediator of DNA damage checkpoint protein 1; NCS -neocarzinostatin; NZ -nocodazole; PTIP, PAX transactivation activation domain-interacting protein; RIF1, Rap1-interacting factor 1 homolog; RNAi, RNA interference; RNF8, RING finger protein 8; RNF168, RING finger protein 168.In response to genotoxic stress, cells protect their genome integrity by activation of a conserved DNA damage response (DDR) pathway that coordinates DNA repair and progression through the cell cycle. Extensive modification of the chromatin flanking the DNA lesion by ATM kinase and RNF8/RNF168 ubiquitin ligases enables recruitment of various repair factors. Among them BRCA1 and 53BP1 are required for homologous recombination and nonhomologous end joining, respectively. Whereas mechanisms of DDR are relatively well understood in interphase cells, comparatively less is known about organization of DDR during mitosis. Although ATM can be activated in mitotic cells, 53BP1 is not recruited to the chromatin until cells exit mitosis. Here we report mitotic phosphorylation of 53BP1 by Plk1 and Cdk1 that impairs the ability of 53BP1 to bind the ubiquitinated H2A and to properly localize to the sites of DNA damage. Phosphorylation of 53BP1 at S1618 occurs at kinetochores and in cytosol and is restricted to mitotic cells. Interaction between 53BP1 and Plk1 depends on the activity of Cdk1. We propose that activity of Cdk1 and Plk1 allows spatiotemporally controlled suppression of 53BP1 function during mitosis.

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Section: Bp1 Is Phosphorylated By Cdk1 and Plk1 In Mitosismentioning

confidence: 91%

Polo-like kinase 1 inhibits DNA damage response during mitosis

et al. 2015

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“…Short-term expo- on May 12, 2018 by guest http://mcb.asm.org/ sure to anisomycin at 2 g/ml is not known to cause DNA damage but strongly induces the p38 signaling pathway in our hands (11). HeLa cells were first synchronized at the G 2 boundary with a CDK1 inhibitor (42) and then released in the presence or absence of anisomycin. Cell cycle progression from G 2 was then monitored up to 6 h after release from the CDK1 inhibitor block.…”

Section: Resultsmentioning

confidence: 99%

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G₂ DNA Damage Checkpoint in Human Cancer Cells

Phong

Horn

et al. 2010

Molecular and Cellular Biology

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p38 mitogen-activated protein kinase (MAPK) is rapidly activated by stresses and is believed to play an important role in the stress response. While Chk1 is known to mediate G 2 DNA damage checkpoint control, p38 was also reported to have an essential function in this checkpoint control. Here, we have investigated further the roles of p38 and Chk1 in the G 2 DNA damage checkpoint in cancer cells. We find that although p38 activation is strongly induced by DNA damage, its activity is not required for the G 2 DNA damage checkpoint. In contrast, Chk1 kinase is responsible for the execution of G 2 DNA damage checkpoint control in p53-deficient cells. The inhibition of p38 activity has no effect on Chk1 activation and ␥-H2AX expression. Global gene expression profiling of cancer cells in response to tumor necrosis factor alpha (TNF-␣) revealed that p38 plays a strong prosurvival role through the coordinated downregulation of proapoptotic genes and upregulation of prosurvival genes. We show that the inhibition of p38 activity during G 2 DNA damage checkpoint arrest triggers apoptosis in a p53-independent manner with a concurrent decrease in the level of Bcl2 family proteins. Our results suggest that although p38 MAPK is not required for the G 2 DNA damage checkpoint function, it plays an important prosurvival role during the G 2 DNA damage checkpoint response through the upregulation of the Bcl2 family proteins.

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“…NRK cells were arrested in G2 using a 20-h treatment with the CDK1 inhibitor RO3306 (Vassilev, 2006). The G2-arrested cells were also treated for 1 h and 4 h prior to fixing, with DMSO (control), with a JNK inhibitor (SP600125) and with inhibitors of MEK1 (U0126) and PLK1 (BI2536), which are two kinases involved in the regulation of Golgi structure (Lin et al, 2000;Feinstein and Linstedt, 2007;Villeneuve et al, 2013).…”

Section: Inhibition Of the Jnk Pathway Blocks Cleavage Of The Golgi Rmentioning

confidence: 99%

JNK2 controls fragmentation of the Golgi complex and the G2/M transition through phosphorylation of GRASP65

Cervigni

Bonavita

Barretta

et al. 2015

Journal of Cell Science

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In mammalian cells, the Golgi complex is composed of stacks that are connected by membranous tubules. During G2, the Golgi complex is disassembled into isolated stacks. This process is required for entry into mitosis, indicating that the correct inheritance of the organelle is monitored by a 'Golgi mitotic checkpoint'. However, the regulation and the molecular mechanisms underlying this Golgi disassembly are still poorly understood. Here, we show that JNK2 has a crucial role in the G2-specific separation of the Golgi stacks through phosphorylation of Ser277 of the Golgistacking protein GRASP65 (also known as GORASP1). Inhibition of JNK2 by RNA interference or by treatment with three unrelated JNK inhibitors causes a potent and persistent cell cycle block in G2. JNK activity becomes dispensable for mitotic entry if the Golgi complex is disassembled by brefeldin A treatment or by GRASP65 depletion. Finally, measurement of the Golgi fluorescence recovery after photobleaching demonstrates that JNK is required for the cleavage of the tubules connecting Golgi stacks. Our findings reveal that a JNK2-GRASP65 signalling axis has a crucial role in coupling Golgi inheritance and G2/M transition.

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Cell Cycle Synchronization at the G₂/M Phase Border by Reversible Inhibition of CDK1

Cited by 158 publications

References 13 publications

Polo-like kinase 1 inhibits DNA damage response during mitosis

Polo-like kinase 1 inhibits DNA damage response during mitosis

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G₂ DNA Damage Checkpoint in Human Cancer Cells

JNK2 controls fragmentation of the Golgi complex and the G2/M transition through phosphorylation of GRASP65

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Cell Cycle Synchronization at the G2/M Phase Border by Reversible Inhibition of CDK1

Cited by 158 publications

References 13 publications

Polo-like kinase 1 inhibits DNA damage response during mitosis

Polo-like kinase 1 inhibits DNA damage response during mitosis

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G2 DNA Damage Checkpoint in Human Cancer Cells

JNK2 controls fragmentation of the Golgi complex and the G2/M transition through phosphorylation of GRASP65

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Cell Cycle Synchronization at the G₂/M Phase Border by Reversible Inhibition of CDK1

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G₂ DNA Damage Checkpoint in Human Cancer Cells