Loss of a yeast telomere: Arrest, recovery, and chromosome loss

Sandell, Lisa L.; Zakian, Virginia A.

doi:10.1016/0092-8674(93)90493-a

Cited by 753 publications

(627 citation statements)

References 35 publications

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“…However, 32 telomere‐free chromosome ends (resembling to as many double strand breaks) did not massively activate this major checkpoint pathway. This result is remarkable because yeast cells usually activate the Rad9–Rad53 pathway in response to a single unrepaired DSB or to a lost telomere (Sandell & Zakian, 1993; Harrison & Haber, 2006) and raised the question of the mechanisms behind this checkpoint tolerance.…”

Section: Resultsmentioning

confidence: 99%

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%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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“…Adaptation to the DNA damage checkpoint in yeast was observed only when a single double-strand break was present (Sandell and Zakian, 1993). Thus, adaptation to the replication checkpoint may occur only in the presence of active DNA synthesis and not in the presence of stalled replication, or perhaps only when a fraction of the replication forks are affected.…”

Section: Discussionmentioning

confidence: 99%

“…Second, the cells with mitotic DNA synthesis activated the S-M phase checkpoint and subsequently experienced checkpoint adaptation. Checkpoint adaptation occurs in cells that are arrested at a DNA checkpoint but eventually over-ride this arrest and re-enter the cell cycle without repair of the damage (Sandell and Zakian, 1993). Therefore, we assayed cells containing chromosomes with DRT/DMC for activation of the replication checkpoint.…”

Section: Dna Synthesis During Mitosismentioning

confidence: 99%

Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability

et al. 2006

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Certain chromosome rearrangements display a significant delay in chromosome replication timing (DRT) that is associated with a subsequent delay in mitotic chromosome condensation (DMC). DRT/DMC chromosomes are common in tumor cells in vitro and in vivo and occur frequently in cells exposed to ionizing radiation. A hallmark for these chromosomes is the delayed phosphorylation of serine 10 of histone H3 during mitosis. The chromosome passenger complex, consisting of multiple proteins including Aurora B kinase and INCENP is thought to be responsible for H3 phosphorylation, chromosome condensation and the subsequent segregation of chromosomes. In this report, we show that chromosomes with DRT/DMC contain phosphorylated Chk1, consistent with activation of the S-M phase checkpoint. Furthermore, we show that INCENP is recruited to the DRT/DMC chromosomes during all phases of mitosis. In contrast, Aurora B kinase is absent on DRT/DMC chromosomes when these chromosomes lack serine 10 phosphorylation of H3. We also show that mitotic arrest deficient 2 (Mad2), a member of the spindle assembly checkpoint, is present on DRT/DMC chromosomes at a time when the normally condensed chromosomes show no Mad2 staining, indicating that DRT/DMC activates the spindle assembly checkpoint. Finally, cells with DRT/ DMC chromosomes have centrosome amplification, abnormal spindle assembly, endoreduplication and significant chromosome instability.

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“…Notably, however neither Nbs1 nor ATM is required for the activation of Chk1 in lymphocytes in response to replication stress Pellegrini et al, 2006). Adaptation mutants in yeast eventually die after 10 divisions due to loss of genetic material (Sandell and Zakian, 1993). Exonucleolytic processing of V(D)J recombination coding ends has been observed in ATM À/À lymphocytes (Bredemeyer et al, 2006), and we also noted a striking degradation of chromosomes in approximately 2/3 of the aberrant metaphases (Callen et al, 2007).…”

Section: Checkpoint Adaptationmentioning

confidence: 70%

“…In yeast, the presence of a single irreparable DSB is not lethal: after initial checkpoint arrest, the broken chromosome can be replicated and persists for up to 10 cell divisions (Sandell and Zakian, 1993;Toczyski et al, 1997;Lee et al, 1998;Kaye et al, 2004). In checkpoint deficient strains (for example RAD9, RAD17 or MEC1 (similar to ATM/ATR)), cells do not even delay the first cycle and they continue to divide despite chromosome loss and genomic instability (Galgoczy and Toczyski, 2001).…”

Section: Checkpoint Adaptationmentioning

confidence: 99%

Breaking down cell cycle checkpoints and DNA repair during antigen receptor gene assembly

Callén

Nussenzweig

2007

Oncogene

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Double-strand breaks (DSBs) are intermediates in several physiological processes including V(D)J and class switch recombination. They are also potent substrates for chromosomal translocations that arise as by-products of antigen receptor gene assembly in lymphocytes. ATM is one among several key proteins involved in the detection, signaling and repair of DNA breaks. Despite redundancies in DSB signaling pathways, it has recently been demonstrated that ATM deficient lymphocytes can survive and proliferate several generations in vitro and in vivo despite harboring terminally deleted chromosomes produced by V(D)J recombination. In this review, we discuss how two complementary genome maintenance functions mediated by ATM prevent lymphocytes from adapting to persistent DNA damage.

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Loss of a yeast telomere: Arrest, recovery, and chromosome loss

Cited by 753 publications

References 35 publications

Rif1 and Exo1 regulate the genomic instability following telomere losses

Rif1 and Exo1 regulate the genomic instability following telomere losses

Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability

Breaking down cell cycle checkpoints and DNA repair during antigen receptor gene assembly

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