The yeast metacaspase is implicated in oxidative stress response in frataxin‐deficient cells

Lefevre, Sophie D.; Sliwa, Dominika; Auchère, Françoise; Brossas, Caroline; Ruckenstuhl, Christoph; Boggetto, Nicole; Lesuisse, Emmanuel; Madeo, Frank; Camadro, Jean‐Michel; Santos, Renata

doi:10.1016/j.febslet.2011.12.002

Cited by 17 publications

(25 citation statements)

References 33 publications

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“…These results led the authors to suggest that the increased spontaneous nuclear damage in Δ yfh1 cells was caused by H 2 O 2 generated in the mitochondria (14). In line with this hypothesis, Δ yfh1 cells are extremely sensitive to H 2 O 2 treatment (21). In addition, different studies in yeast, Drosophila and patient fibroblasts showed that H 2 O 2 levels increase in frataxin-deficient cells (22–24).…”

Section: Introductionmentioning

confidence: 72%

Apn1 AP-endonuclease is essential for the repair of oxidatively damaged DNA bases in yeast frataxin-deficient cells

Lefevre¹,

Brossas²,

Auchère³

et al. 2012

Human Molecular Genetics

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Frataxin deficiency results in mitochondrial dysfunction and oxidative stress and it is the cause of the hereditary neurodegenerative disease Friedreich ataxia (FA). Here, we present evidence that one of the pleiotropic effects of oxidative stress in frataxin-deficient yeast cells (Δyfh1 mutant) is damage to nuclear DNA and that repair requires the Apn1 AP-endonuclease of the base excision repair pathway. Major phenotypes of Δyfh1 cells are respiratory deficit, disturbed iron homeostasis and sensitivity to oxidants. These phenotypes are weak or absent under anaerobiosis. We show here that exposure of anaerobically grown Δyfh1 cells to oxygen leads to down-regulation of antioxidant defenses, increase in reactive oxygen species, delay in G1- and S-phases of the cell cycle and damage to mitochondrial and nuclear DNA. Nuclear DNA lesions in Δyfh1 cells are primarily caused by oxidized bases and single-strand breaks that can be detected 15–30 min after oxygen exposition. The Apn1 enzyme is essential for the repair of the DNA lesions in Δyfh1 cells. Compared with Δyfh1, the double Δyfh1Δapn1 mutant shows growth impairment, increased mutagenesis and extreme sensitivity to H2O2. On the contrary, overexpression of the APN1 gene in Δyfh1 cells decreases spontaneous and induced mutagenesis. Our results show that frataxin deficiency in yeast cells leads to increased DNA base oxidation and requirement of Apn1 for repair, suggesting that DNA damage and repair could be important features in FA disease progression.

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Section: Introductionmentioning

confidence: 72%

Apn1 AP-endonuclease is essential for the repair of oxidatively damaged DNA bases in yeast frataxin-deficient cells

Lefevre¹,

Brossas²,

Auchère³

et al. 2012

Human Molecular Genetics

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“…This suggests thus that the endopeptidase activity of Mca1p may directly degrade or at least impair mitochondria. This is relevant to a previously unexplained observation that deleting YCA1 from a frataxin-deficient yfh1⌬ strain that exhibits severe mitochondrial dysfunctions, allows the restoration of cytochromes assembly (49). YCA1 deletion may lower the rate of mitochondria degradation and thereby allow the synthesis and maintenance of partly functional mitochondria.…”

Section: Discussionmentioning

confidence: 96%

The Metacaspase (Mca1p) has a Dual Role in Farnesol-induced Apoptosis in Candida albicans

Léger

Garcia

Ounissi

et al. 2015

Molecular & Cellular Proteomics

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Manipulating the apoptotic response of Candida albicans may help in the control of this opportunistic pathogen. The metacaspase Mca1p has been described as a key protease for apoptosis in C. albicans but little is known about its cleavage specificity and substrates. We therefore initiated a series of studies to describe its function. We used a strain disrupted for the MCA1 gene (mca1⌬/⌬) and compared its proteome to that of a wild-type isogenic strain, in the presence and absence of a known inducer of apoptosis, the quorum-sensing molecule farnesol. Labelfree and TMT labeling quantitative proteomic analyses showed that both mca1 disruption and farnesol treatment significantly affected the proteome of the cells. The combination of both conditions led to an unexpected biological response: the strong overexpression of proteins implicated in the general stress. We studied sites cleaved by Mca1p using native peptidomic techniques, and a bottom-up approach involving GluC endoprotease: there appeared to be a "K/R" substrate specificity in P1 and a "D/E" specificity in P2. We also found 77 potential substrates of Mca1p, 13 of which validated using the most stringent filters, implicated in protein folding, protein aggregate resolubilization, glycolysis, and a number of mitochondrial functions. An immunoblot assay confirmed the cleavage of Ssb1p, a member of the HSP70 family of heat-shock proteins, in conditions where the metacaspase is activated. These various results indicate that Mca1p is involved in a limited and specific proteolysis program triggered by apoptosis. One of the main functions of Mca1p appears to be the degradation of several major heat-shock proteins, thereby contributing to weakening cellular defenses and amplifying the cell death process. Finally, Mca1p appears to contribute significantly to the control of mitochondria biogenesis and deg-

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“…A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 20 Recent advances in various ‗omics' technologies enable quantitative monitoring of the abundance of various biological molecules in a high-throughput manner, and thus allow determination of their variations between different biological states. In this study the integration of proteomics and metabolomics, has proved a potent tool of investigation on AA-PCD mechanisms dependent or independent on YCA1 and it will prove pivotal for understanding how the individual components in the system interact and influence overall cell metabolism and ultimately its fate.…”

Section: Discussionmentioning

confidence: 99%

Proteome and metabolome profiling of wild-type and YCA1 -knock-out yeast cells during acetic acid-induced programmed cell death

Longo

Ždralević

Guaragnella

et al. 2015

Journal of Proteomics

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The yeast metacaspase is implicated in oxidative stress response in frataxin‐deficient cells

Cited by 17 publications

References 33 publications

Apn1 AP-endonuclease is essential for the repair of oxidatively damaged DNA bases in yeast frataxin-deficient cells

Apn1 AP-endonuclease is essential for the repair of oxidatively damaged DNA bases in yeast frataxin-deficient cells

The Metacaspase (Mca1p) has a Dual Role in Farnesol-induced Apoptosis in Candida albicans

Proteome and metabolome profiling of wild-type and YCA1 -knock-out yeast cells during acetic acid-induced programmed cell death

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