Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast
ABSTRACT Inactivation of the budding yeast telomere binding protein Cdc13 results in abnormal telomeres (exposed long G-strands) and activation of the DNA damage checkpoint. In the current study, we show that inactivation of Cdc13p induces apoptotic signals in yeast, as evidenced by caspase activation, increased reactive oxygen species production, and flipping of phosphatidylserine in the cytoplasmic membrane. These apoptotic signals were suppressed in a mitochondrial (rho(o)) mutant. Moreover, mitochondrial proteins (e.g. MTCO3) were identified as multicopy suppressors of cdc13-1, suggesting the involvement of mitochondrial functions in telomere-initiated apoptotic signaling. These telomere-initiated apoptotic signals were also shown to depend on MEC1, but not TEL1, and were antagonized by MRE11. Our results are consistent with a model in which single-stranded G-tails in the cdc13-1 mutant trigger MEC1-dependent apoptotic signaling in yeast.
- SourceAvailable from: Fábio Faria-Oliveira
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- "GUP1 is involved in a wide range of cellular processes, some of which are associated directly or indirectly with apoptosis, such as rafts integrity and lipids metabolism [17,18,21,30,31,34], cytoskeleton polarization [35,37], and telomere length [36,38]. In the present work, we assess apoptotic markers for gup1∆ mutant strain and compare them with Wt, under two different conditions documented to induce apoptosis in yeast: chronological aging and acetic acid [8,39]. "
ABSTRACT: During the past years, yeast has been successfully established as a model to study mechanisms of programmed cell death regulation. Saccharomyces cerevisiae commits to cell death showing typical hallmarks of metazoan apoptosis, in response to different stimuli. Gup1p, an O-acyltransferase, is required for several cellular processes that are related to apoptosis development, such as rafts integrity and stability, lipid metabolism including GPI anchor correct remodeling, proper mitochondrial and vacuole function, bud site selection and actin dynamics. Therefore, we hypothesize that apoptotic process would be affected by GUP1 deletion. In the present work we used two known apoptosis inducing conditions, chronological aging and acetic acid, to assess several apoptotic markers in gup1∆ mutant strain. We found that this mutant presents a significantly reduced chronological lifespan as compared to Wt and it is also highly sensitive to acetic acid treatment. In addition, it presents extremely high levels of ROS. There were notorious differences on apoptotic markers between Wt and gup1∆ mutant strains, namely on the maintenance of plasma membrane integrity, on the phosphatidylserine externalization, on the depolarization of mitochondrial membrane and on the chromatin condensation. Those suggested that the mutant, under either condition, probably dies of necrosis and not from apoptosis. To Gup1p has been assigned an important function on lipid rafts assembly/integrity, lipid metabolism and GPI anchor remodeling. Our results provide, for the first time, the connection of the integrity of yeast lipid rafts and apoptosis induction and/or signaling, giving new insights into the molecular mechanisms underlying this process in yeast.BMC Microbiology 05/2012; 12(1):80. DOI:10.1186/1471-2180-12-80 · 2.98 Impact Factor
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- "Release of cyt c was also shown in cells treated with amiodarone , H 2 O 2  and in asf1/cia1Δ  or Cdc48 S565G mutants . Complexes III and IV were found to be involved in death induced by amiodarone  or abnormal telomeres (cdc13Δ) , respectively, while deletion of different genes encoding proteins from the electron transport chain rendered cells more sensitive to apoptosis induced by overexpression of yeast Aifhomologous mitochondrion-associated inducer of death (AMID) orthologue, NDI1 . Formation of petites was shown to accompany apoptotic cell death induced by glucose (2%, w/v) in the absence of additional nutrients . "
ABSTRACT: Mitochondrial involvement in yeast apoptosis is probably the most unifying feature in the field. Reports proposing a role for mitochondria in yeast apoptosis present evidence ranging from the simple observation of ROS accumulation in the cell to the identification of mitochondrial proteins mediating cell death. Although yeast is unarguably a simple model it reveals an elaborate regulation of the death process involving distinct proteins and most likely different pathways, depending on the insult, growth conditions and cell metabolism. This complexity may be due to the interplay between the death pathways and the major signalling routes in the cell, contributing to a whole integrated response. The elucidation of these pathways in yeast has been a valuable help in understanding the intricate mechanisms of cell death in higher eukaryotes, and of severe human diseases associated with mitochondria-dependent apoptosis. In addition, the absence of obvious orthologues of mammalian apoptotic regulators, namely of the Bcl-2 family, favours the use of yeast to assess the function of such proteins. In conclusion, yeast with its distinctive ability to survive without respiration-competent mitochondria is a powerful model to study the involvement of mitochondria and mitochondria interacting proteins in cell death.Biochimica et Biophysica Acta 08/2008; 1783(7):1286-302. DOI:10.1016/j.bbamcr.2008.03.010 · 4.66 Impact Factor
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- "Several studies have shown that DNA damage stimulates apoptosis in budding yeast. Mutation in CDC13, for example, triggers apoptotic cell death due to the accumulation of DNA damage . UV radiation also induces some features of apoptosis . "
ABSTRACT: Cohesin is a protein complex that regulates sister chromatid cohesin during cell division. Malfunction in chromatid cohesin results in chromosome missegregation and aneuploidy. Here, we report that mutations of MCD1 and PDS5, two major components of cohesin in budding yeast, cause apoptotic cell death, which is characterized by externalization of phosphatidylserine at cytoplasmic membrane, chromatin condensation and fragmentation, and ROS production. Microarray analysis suggests that the cell death caused by mutation of MCD1 or PDS5 is due to the internal stress response, contrasting to the environmental or external stress response induced by external stimuli, such as hydrogen peroxide. A common feature shared by the internal stress response and external stress response is the response to stimulus, including response to DNA damage, mitochondria functions, and oxidative stress, which play an important role in yeast apoptotic cell death.Comparative and Functional Genomics 02/2008; 2008:634283. DOI:10.1155/2008/634283 · 1.75 Impact Factor