The centrosome and the DNA damage induced checkpoint

Fletcher, Lynda; Muschel, Ruth J.

doi:10.1016/j.canlet.2006.01.006

Cited by 23 publications

(28 citation statements)

References 66 publications

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“…Numerous studies involve the centrosome in the progression between different cell cycle phases (reviewed in refs. [10][11][12][13][14][15][16]. However, there is a debate concerning the role of the centrosome in the control of the G 1 to S phase transition.…”

Section: Introductionmentioning

confidence: 99%

The centrosomal FOP protein is required for cell cycle progression and survival

Acquaviva

Chevrier²,

Chauvin³

et al. 2009

Cell Cycle

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Cell Cycle 1217FOP is a centrosomal protein originally discovered as a fusion partner of FGFR1 in patients with a rare stem cell myeloproliferative disorder. In DT40 chicken lymphocytes, we show that the normal FOP protein localizes at the centrosome throughout the cell cycle and preferentially accumulates at the distal end of the mother centriole. We used homologous recombination in DT40 cells to generate an inducible null mutant for FOP. Loss of FOP induces apoptosis in the G 1 phase of the cell cycle with accumulation of a 32 kDa P53 tumor suppressor isoform and NOXA and FAS transcripts. However, centrosome integrity and microtubule organization are conserved without FOP and mitotic division and cytokinesis are as efficient as in control cells. Our results suggest that FOP is involved in G 1 to S signaling and thus in proliferation/death fate. Several reports show that centrosome alteration can lead to an arrest in G 1 and, possibly, to senescence in a fraction of cells. The phenotype we observed is more severe in FOP null cells. This could be dependent on the cell context or on the efficiency of a knock out that allows the complete disappearance of the target protein and prevents any de novo synthesis. This is an important observation in regard to the current discussion of what consequence centrosome perturbation could have on a cell and shows that a centrosomal protein can be necessary for cell cycle progression and survival.

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Section: Introductionmentioning

confidence: 99%

The centrosomal FOP protein is required for cell cycle progression and survival

Acquaviva

Chevrier²,

Chauvin³

et al. 2009

Cell Cycle

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“…The development of centrosome abnormalities in tumorigenesis may result from various situations, including exposure to genotoxic agents, cell stress, oncogenic virus, mutation of oncogenes and tumor suppressor genes such as p53, BRCA1 or ATM (Morris et al, 2000;Fukasawa, 2005;McPherson et al, 2006). At the same time, the signaling machinery involved in DNA damage response has been clearly determined to play a critical role in the process of centrosome amplification (Fletcher and Muschel, 2006;Loffler et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Localization of TEIF in the centrosome and its functional association with centrosome amplification in DNA damage, telomere dysfunction and human cancers

et al. 2009

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“…Higher eukaryotes have multiple Cdks (Cdk1 to Cdk11) with more specialized roles, but Cdk1 and its role in promoting mitosis have been conserved. In the normal cell cycle, mitotic cyclins (cyclins A, B, and B3) accumulate during G 2 , and Cdk1 is held in a relatively inactive state by inhibitory phosphorylation at residues Tyr 15 (in fission yeast) or Thr 14 and Tyr 15 (higher eukaryotes). Two kinases (Myt1 and Wee1) and one phosphatase (Cdc25) determine the phosphorylation status of these residues, and, together with Cdk1, these are thought to constitute a molecular switch that commits cells to undergo mitosis.…”

mentioning

confidence: 99%

“…entry into mitosis before DNA replication is complete, resulting in aberrant mitosis and cell death) (11,12). In a variety of systems, mutation of Cdk1 inhibitory phosphorylation sites also impairs G 2 arrest in response to genotoxic damage, indicative of signaling pathways that sense such damage and culminate in the inhibitory phosphorylation of Cdk1 (13)(14)(15). Despite the crucial role that inhibitory phosphorylation of Cdk1 undoubtedly plays in regulating the G 2 /M transition, it remains unclear whether the autocatalytic burst of Cdk1 activity that accompanies Cdk1 dephosphorylation is absolutely required to promote the G 2 /M transition or whether relief from other inhibitory mechanisms can suffice.…”

mentioning

confidence: 99%

Rescue of a Human Cell Line from Endogenous Cdk1 Depletion by Cdk1 Lacking Inhibitory Phosphorylation Sites

Gupta

Trott

Porter

2007

Journal of Biological Chemistry

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Cells that transiently overexpress cyclin-dependent kinase 1 lacking inhibitory phosphorylation sites (Cdk1-AF) undergo premature and catastrophic mitosis, reflecting the key role for Cdk1 in promoting a timely transit from G 2 into mitosis. Conversely, cells depleted of Cdk1 undergo repeated S phases without intervening mitoses (endoreduplication), reflecting a role for Cdk1 in preventing premature S phases. It is not known how Cdk1 prevents entry into S phase at times in G 2 when it does not promote mitosis. Also uncertain is the extent of redundancy between inhibitory phosphorylation and other mechanisms for controlling Cdk1 activity. We describe here human cells that not only tolerate stable Cdk1-AF expression but also rely on it for survival when endogenous Cdk1 is depleted. When residual endogenous Cdk1 expression is further depleted, however, proliferation of Cdk1-AF-rescued cells is inhibited. Interestingly, this inhibition is not accompanied by endoreduplication. These results are consistent with a two-threshold model for Cdk1 kinase activity, one for suppressing endoreduplication and one for promoting mitosis. They also indicate that inhibitory phosphorylation is indispensable for only a fraction of the total cellular complement of Cdk1. Cyclin-dependent kinases (Cdks)4 control eukaryotic cell cycle progression, ensuring that each phase occurs in an orderly and timely manner (1-3). To be active, Cdks must be bound to an appropriate cyclin molecule and free from inhibition by Cdk inhibitors. Their action can be further controlled by changes in subcellular localization and phosphorylation state. Cdks therefore have a variety of ways in which their activity can be modulated in response to extrinsic (e.g. presence of growth factor) or intrinsic (e.g. completion of DNA synthesis) cues (4 -8).Transitions from G 2 to mitosis and from G 1 into S phase are key cell cycle control points. Simple eukaryotes have a single Cdk (Cdk1, or Cdc2 and Cdc28 in budding and fission yeast, respectively) that controls both of these transitions. Higher eukaryotes have multiple Cdks (Cdk1 to Cdk11) with more specialized roles, but Cdk1 and its role in promoting mitosis have been conserved. In the normal cell cycle, mitotic cyclins (cyclins A, B, and B3) accumulate during G 2 , and Cdk1 is held in a relatively inactive state by inhibitory phosphorylation at residues Tyr 15 (in fission yeast) or Thr 14 and Tyr 15 (higher eukaryotes). Two kinases (Myt1 and Wee1) and one phosphatase (Cdc25) determine the phosphorylation status of these residues, and, together with Cdk1, these are thought to constitute a molecular switch that commits cells to undergo mitosis. Thus, in late G 2 , the sudden increase in Cdk1 activity that coincides with entry into mitosis is thought to be achieved by a double positive feedback loop in which Cdk1 kinase activity both inhibits Wee1 kinase and activates Cdc25 phosphatase (9). The resulting flood of Cdk1 activity promotes mitosis by phosphorylating a range of nuclear substrates (e.g. lamins and histone H3...

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The centrosome and the DNA damage induced checkpoint

Cited by 23 publications

References 66 publications

The centrosomal FOP protein is required for cell cycle progression and survival

The centrosomal FOP protein is required for cell cycle progression and survival

Localization of TEIF in the centrosome and its functional association with centrosome amplification in DNA damage, telomere dysfunction and human cancers

Rescue of a Human Cell Line from Endogenous Cdk1 Depletion by Cdk1 Lacking Inhibitory Phosphorylation Sites

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