Regulation of Saccharomyces Rad53 Checkpoint Kinase during Adaptation from DNA Damage–Induced G2/M Arrest

Pellicioli, Achille; Lee, Sang Eun; Lucca, Chiara; Foiani, Marco; Haber, James E.

doi:10.1016/s1097-2765(01)00177-0

Cited by 275 publications

(340 citation statements)

References 36 publications

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“…5). We also tested the casein kinase component Ckb2 because it is involved in checkpoint adaptation, a process by which checkpoint pathways adapt to and ‘ignore’ an unrepaired DNA double strand break (Toczyski et al ., 1997; Pellicioli et al ., 2001). …”

Section: Resultsmentioning

confidence: 99%

“…Almost all cells arrested proliferation within 4 h following induction of the DSB, but later underwent checkpoint adaptation (e.g. they started to divide again), consistent with previous reports (Lee et al ., 1998; Pellicioli et al ., 2001). Up to 50% of the GAL‐HO cells (marked as wild‐type) adapted by 14 h after the DSB induction (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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SummaryTelomere attrition is linked to cancer, diabetes, cardiovascular disease and aging. This is because telomere losses trigger further genomic modifications, culminating with loss of cell function and malignant transformation. However, factors regulating the transition from cells with short telomeres, to cells with profoundly altered genomes, are little understood. Here, we use budding yeast engineered to lack telomerase and other forms of telomere maintenance, to screen for such factors. We show that initially, different DNA damage checkpoint proteins act together with Exo1 and Mre11 nucleases, to inhibit proliferation of cells undergoing telomere attrition. However, this situation changes when survivors lacking telomeres emerge. Intriguingly, checkpoint pathways become tolerant to loss of telomeres in survivors, yet still alert to new DNA damage. We show that Rif1 is responsible for the checkpoint tolerance and proliferation of these survivors, and that is also important for proliferation of cells with a broken chromosome. In contrast, Exo1 drives extensive genomic modifications in survivors. Thus, the conserved proteins Rif1 and Exo1 are critical for survival and evolution of cells with lost telomeres.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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“…Checkpoint adaptation, originally described in budding yeast, describes a process in which checkpoint-induced cell cycle arrest eventually is released in the presence of unrepaired DNA damage (26). Orthologues of PLK1 contribute to the inactivation of the checkpoint pathway to bring about adaptation (27,28). Our experiments and those involving checkpoint adaptation involve processes, which are different from checkpoint recovery in which the checkpoint is inactivated due to repair of the initial damage.…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 92%

Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit

Bekier

Fischbach

Lee

et al. 2009

Molecular Cancer Therapeutics

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Cell death induced by agents that disrupt microtubules can kill cells by inducing a prolonged mitotic block. This mitotic block is dependent on the spindle assembly checkpoint, a surveillance system that ensures the bipolar attachment of chromosomes to the mitotic spindle before the onset of anaphase. Under some conditions, the spindle assembly checkpoint can become weakened, allowing cells to exit mitosis despite the presence of chromosomes that are not properly attached to the mitotic spindle. Here, we use an Aurora kinase inhibitor to drive mitotic exit and test the effect of mitotic arrest length on death in the subsequent interphase. Cells that are blocked in mitosis for >15 h die shortly after exiting from mitosis, whereas cells that exit after being blocked for <15 h show variable fates, with some living for days after exiting mitosis. Cells blocked in mitosis by either Taxol or epothilone B are acutely sensitive to the death ligand tumor necrosis factor-related apoptosisinducing ligand, suggesting that prolonged mitosis allows the gradual accumulation of internal death signals, rendering cells hypersensitive to additional prodeath cues. Death under these conditions is initiated while cyclin B1 is still present, indicating that cells are in mitosis. Our experiments suggest that there is a point of no return during prolonged mitotic block after which mitotic exit can no longer block death.

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“…Rather than arresting cells at the G2/M transition, Rad53 blocks the metaphase-anaphase transition through regulation of the Separase inhibitor Pds1 (Securin) [26][27][28]. Cells lacking Pph3 show persistent Rad53 activation, and thus a delay in recovery from a checkpoint arrest caused by an HO-endonuclease induced DSB [23].…”

Section: Dephosphorylation Of Other Checkpoint Proteinsmentioning

confidence: 99%

Turning off the G2 DNA damage checkpoint

Calonge

O’Connell

2008

DNA Repair

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In response to DNA damage, cells activate checkpoints to delay cell cycle progression and allow time for completion of DNA repair before commitment to S-phase or mitosis. During G2, many proteins collaborate to activate Chk1, an effector protein kinase that ensures the mitotic cyclindependent kinase remains in an inactive state. This checkpoint is ancient in origin and highly conserved from fission yeast to humans. Work from many groups has led to a detailed description of the spatiotemporal control of signaling events leading to Chk1 activation. However, to survive DNA damage in G2, the checkpoint must be inactivated to allow resumption of cell cycling and entry into mitosis. Though only beginning to be understood, here we review current data regarding checkpoint termination signals acting on Chk1 and its' upstream regulators.

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Regulation of Saccharomyces Rad53 Checkpoint Kinase during Adaptation from DNA Damage–Induced G2/M Arrest

Cited by 275 publications

References 36 publications

Rif1 and Exo1 regulate the genomic instability following telomere losses

Rif1 and Exo1 regulate the genomic instability following telomere losses

Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit

Turning off the G2 DNA damage checkpoint

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