Cell cycle re-entry mechanisms after DNA damage checkpoints: Giving it some gas to shut off the breaks!

Vugt, Marcel A.T.M. van; Yaffe, Michael B.

doi:10.4161/cc.9.11.11840

Cited by 21 publications

(17 citation statements)

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“…Long-time-course experiments in which HeLa cells were treated with DOXO for 24 hr, followed by drug washout, revealed that the most dramatic Golgi dispersal persisted for at least 5 days (Figure S2A). Moreover, the Golgi remained detectably dispersed at least 30 days after the initial DNA damage occurred (Figure 2B), at a time when cell proliferation has completely recovered (van Vugt and Yaffe, 2010). …”

Section: Resultsmentioning

confidence: 99%

“…The response occurs quickly and is detectable within 4 hr after exposure to DNA-damaging agents, yet it also persists for weeks after transient exposure to DNA-damaging agents. This persistence could be due to the stability of a small number of DNA breaks that continue to activate the pathway (van Vugt and Yaffe, 2010) or it may indicate the existence of a positive feedback loop that maintains the Golgi dispersal once it is initiated.…”

Section: Discussionmentioning

confidence: 99%

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DNA Damage Triggers Golgi Dispersal via DNA-PK and GOLPH3

Farber-Katz

Dippold

Buschman

et al. 2014

Cell

199

272

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SUMMARY The response to DNA damage, which regulates nuclear processes such as DNA repair, transcription, and cell cycle, has been studied thoroughly. However, the cytoplasmic response to DNA damage is poorly understood. Here, we demonstrate that DNA damage triggers dramatic reorganization of the Golgi, resulting in its dispersal throughout the cytoplasm. We further show that DNA-damage-induced Golgi dispersal requires GOLPH3/MYO18A/F-actin and the DNA damage protein kinase, DNA-PK. In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas over-expression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents. Identification of the DNA-damage-induced Golgi response reveals an unexpected pathway through DNA-PK, GOLPH3, and MYO18A that regulates cell survival following DNA damage.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DNA Damage Triggers Golgi Dispersal via DNA-PK and GOLPH3

Farber-Katz

Dippold

Buschman

et al. 2014

Cell

199

272

View full text Add to dashboard Cite

show abstract

“…56 In certain model organisms, such as budding yeast and frog, after a prolonged arrest, cells can enter mitosis even with unrepaired DNA lesions. This process is called DNA damage adaptation, 57 and the DNA damage mediator Claspin has been shown to regulate the DNA damage adaptation process. 58 It is worth noting that Claspin also interacts with PLK1.…”

Section: Discussionmentioning

confidence: 99%

“…Because the kinase activity of CDK1/cyclin B1, Aurora A, and PLK1 are all downregulated by DNA damage (Fig. 4C), 4,57 they are less likely to be the contributing kinases. Therefore, checkpoint kinases such as ATR and Chk1 could be the potential candidates.…”

Section: Disclosure Of Potential Conflicts Of Interestmentioning

confidence: 99%

BRCA1 downregulates the kinase activity of Polo-like kinase 1 in response to replication stress

et al. 2013

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In response to DNA damage or replication stress, proliferating cells are arrested at different cell cycle stages for DNA repair by downregulating the activity of both the cyclin-dependent kinases (CDKs) and other important cell cycle kinases, including Polo-like kinase 1 (PLK1) . The signaling pathway to inhibit CDKs is relatively well understood, and breast cancer gene 1 (BRCA1) and other DNA damage response (DDR) factors play a key role in this process. However, the DNA damage-induced inhibition of PLK1 is still largely a mystery. Here we show that DNA damage and replication stress stimulate the association between BRCA1 and PLK1. Most importantly, we demonstrate that BRCA1 downregulates the kinase activity of PLK1 by modulating the dynamic interactions of Aurora A, hBora, and PLK1. Together with previous findings, we propose that in response to replication stress and DNA damage, BRCA1 plays a critical role in downregulating the kinase activity of both CDKs and PLK1.

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“…These types of simulations can be used to help guide experimental investigation as well as verify that our understanding of the protein-protein interactions underlying the G2 to M transition and G2 arrest mechanism is correct. The model not only recapitulates the published behaviors of the G2 to M transition and DNA damage G2 checkpoint (Rieder, 2011; van Vugt and Yaffe, 2010; van Vugt et al, 2010) but also predicts a novel regulation of intracellular trafficking of MPF that requires pkMyt1.…”

Section: Introductionmentioning

confidence: 68%

A predictive mathematical model of the DNA damage G2 checkpoint

Kesseler

Blinov

Elston

et al. 2013

Journal of Theoretical Biology

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A predictive mathematical model of the transition from the G2 phase in the cell cycle to mitosis (M) was constructed from the known interactions of the proteins that are thought to play significant roles in the G2 to M transition as well as the DNA damage- induced G2 checkpoint. The model simulates the accumulation of active cyclin B1/Cdk1 (MPF) complexes in the nucleus to activate mitosis, the inhibition of this process by DNA damage, and transport of component proteins between cytoplasm and nucleus. Interactions in the model are based on activities of individual phospho-epitopes and binding sites of proteins involved in G2/M. Because tracking phosphoforms leads to combinatorial explosion, we employ a rule-based approach using the BioNetGen software. The model was used to determine the effects of depletion or over-expression of selected proteins involved in the regulation of the G2 to M transition in the presence and absence of DNA damage. Depletion of Plk1 delayed mitotic entry and recovery from the DNA damage-induced G2 arrest and over-expression of MPF attenuated the DNA damage-induced G2 delay. The model recapitulates the G2 delay observed in the biological response to varying levels of a DNA damage signal. The model produced the novel prediction that depletion of pkMyt1 results in an abnormal biological state in which G2 cells with DNA damage accumulate inactive nuclear MPF. Such a detailed model may prove useful for predicting DNA damage G2 checkpoint function in cancer and, therefore, sensitivity to cancer therapy.

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Cell cycle re-entry mechanisms after DNA damage checkpoints: Giving it some gas to shut off the breaks!

Cited by 21 publications

References 0 publications

DNA Damage Triggers Golgi Dispersal via DNA-PK and GOLPH3

DNA Damage Triggers Golgi Dispersal via DNA-PK and GOLPH3

BRCA1 downregulates the kinase activity of Polo-like kinase 1 in response to replication stress

A predictive mathematical model of the DNA damage G2 checkpoint

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