CDC5 and CKII Control Adaptation to the Yeast DNA Damage Checkpoint

Toczyski, David P.; Galgoczy, David J.; Hartwell, Leland H.

doi:10.1016/s0092-8674(00)80375-x

Cited by 411 publications

(468 citation statements)

References 41 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%

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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%

“…Up to 50% of the GAL‐HO cells (marked as wild‐type) adapted by 14 h after the DSB induction (Fig. 6B), whereas only 25% cdc5‐ad cells, known as adaptation‐defective (Toczyski et al ., 1997) adapted. In contrast, 80% ADH1‐RIF1 cells adapted by 14 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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“…Cdc9p competes with DNA pol delta complex for PCNA binding, resulting in replication fork stalling, and it was inferred to decrease the free PCNA pool that might be necessary for other PCNA-binding proteins. Similarly, Rad2p-PCNA interaction could inhibit PCNA binding to other proteins, including Rad9p, thereby causing checkpoint adaptation, a phenomenon in which cells resume mitosis after prolonged cell cycle arrest despite unrepaired DNA damage (Bartek and Lukas, 2007;Schärer, 2008;Toczyski et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Mitotic catastrophe induced by overexpression of budding yeast Rad2p

Kang

Lim

et al. 2010

Yeast

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Mitotic catastrophe provokes endopolyploidy, giant cell formation and, eventually, delayed cell death. Mitotic catastrophe is induced by defective cell cycle checkpoints and by some anticancer drugs, ionizing radiation and microtubule-destabilizing agents. RAD2 is a yeast homologue of XPG, which is a human endonuclease involved in nucleotide excision repair. Here we show that Rad2p overexpression alone, in the absence of extrinsic DNA damage, causes cell growth arrest and mitotic catastrophe. Interestingly, Rad2p-induced cell growth arrest is not caused by the catalytic activity of Rad2p but rather by its C-terminal region. Cells growth-arrested by Rad2p induction do not show apoptotic phenotypes and deletion of YCA1, a yeast caspase homologue, does not affect cell growth arrest by Rad2p induction. However, Rad2p-induced cell growth arrest is released by rad9 deletion but is not affected by downstream DNA damage checkpoint genes. These observations suggest that RAD2 has a function in coordinating cell cycle regulation and damaged DNA repair.

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“…Historically, the first experimental system involved the creation of persistent or irrepairable DNA damage at specific regions of chromosomes, such as telomeres (generated by defective telomere-protection systems; Sandell and Zakian 1993;Toczyski et al 1997) and/or meganucleasespecific cleavage sites introduced at unique positions in the genome (Lee et al 1998;Sandell and Zakian 1993). Although this type of damage affects only part of the genome, it can nevertheless induce a strong checkpoint response by virtue of the fact that the lesions-DNA double-strand breaks-are continually being re-introduced and/or their repair is being prevented using genetic tools such as conditional expression of meganucleases or temperature-sensitive effectors of telomere biogenesis (Lee et al 1998;Sandell and Zakian 1993;Toczyski et al 1997). These systems have been primarily used in non-mammalian model organisms because of the general ease of creating conditional genetic modifications in these organisms.…”

Section: The Adaptation Responsementioning

confidence: 99%

When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage

Serrano

D’Amours

2014

Syst Synth Biol

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The drive to proliferate and the need to maintain genome integrity are two of the most powerful forces acting on biological systems. When these forces enter in conflict, such as in the case of cells experiencing DNA damage, feedback mechanisms are activated to ensure that cellular proliferation is stopped and no further damage is introduced while cells repair their chromosomal lesions. In this circumstance, the DNA damage response dominates over the biological drive to proliferate, and may even result in programmed cell death if the damage cannot be repaired efficiently. Interestingly, the drive to proliferate can under specific conditions overcome the DNA damage response and lead to a reactivation of the proliferative program in checkpoint-arrested cells. This phenomenon is known as adaptation to DNA damage and is observed in all eukaryotic species where the process has been studied, including normal and cancer cells in humans. Polo-like kinases (PLKs) are critical regulators of the adaptation response to DNA damage and they play key roles at the interface of cell cycle and checkpoint-related decisions in cells. Here, we review recent progress in defining the specific roles of PLKs in the adaptation process and how this conserved family of eukaryotic kinases can integrate the fundamental need to preserve genomic integrity with effective cellular proliferation.

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CDC5 and CKII Control Adaptation to the Yeast DNA Damage Checkpoint

Cited by 411 publications

References 41 publications

Rif1 and Exo1 regulate the genomic instability following telomere losses

Rif1 and Exo1 regulate the genomic instability following telomere losses

Mitotic catastrophe induced by overexpression of budding yeast Rad2p

When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage

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