A pathway of targeted autophagy is induced by DNA damage in budding yeast

Eapen, Vinay V.; Waterman, David P.; Bernard, Amélie; Schiffmann, Nathan; Sayas, Enric; Kamber, Roarke A.; Lemos, Brenda; Memisoglu, Gonen; Ang, Jessie; Mazella, Allison; Chuartzman, Silvia; Loewith, Robbie; Schuldiner, Maya; Denic, Vladimir; Klionsky, Daniel J.; Haber, James E.

doi:10.1073/pnas.1614364114

Cited by 57 publications

(71 citation statements)

References 68 publications

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“…The role of autophagy in carcinogenesis is context-dependent. It was demonstrated that the induction of autophagy is associated with DNA damage (55)(56)(57). Autophagy has been shown to regulate some of the DNA repair proteins after DNA damage (55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

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2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Górska‐Ponikowska

Kuban–Jankowska

Daca

et al. 2017

CGP

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Abstract. Background Cancer cells are traditionally characterized by increased glucose uptake, high rates of aerobic glycolysis, increased lactic acid production, impaired mitochondrial function and decreased extracellular pH. These characteristics are known as the 'Warburg effect' (1-3). The 'Warburg effect' is also observed in cancer-associated fibroblasts and mesenchymal stem cells (1-11), which secrete lactate and ketones into the microenvironment of the tumor. Lactic acid exists as L-and D-optical isomers. In mammals including humans, lactate is present almost entirely as L-lactate (12, 13). Interestingly, a variety of human cancer cell lines and human tumors, including breast, prostate, head, neck, and osteosarcoma cancers, import these metabolites and deliver them to the mitochondrial TCA cycle, thereby promoting ATP generation and cell proliferation (1-14). According to this 'reverse Warburg effect', tumor cells can induce metabolic reprogramming by shuttling lactate as an energy source to neighboring cancer cells, to the adjacent stroma and to vascular endothelial cells (1,14).Tumors contain both aerobic and hypoxic regions that form a metabolic symbiosis that is crucial for tumor cell survival (15, 16). The cancer cells located in the hypoxic regions export lactate, which acidifies the tumor environment; the cells located in the aerobic regions, however, import lactate and utilize it for oxidative phosphorylation (4). Bonuccelli and colleagues (2) suggested that L-lactate metabolism in cancer cells may explain why diabetic patients have an increased risk of cancer development and a tendency towards autophagy/mitophagy in their adipose tissue. An increased tumor L-lactate level strictly correlates with increased metastasis, tumor recurrence and poor outcome (6-9).L-lactate metabolism and the reverse Warburg effect has been clearly established in osteosarcoma cells. It has been demonstrated that the secretion of lactate and ketones by the mesenchymal stem cells drives mitochondrial biogenesis and increases the mitochondrial activity in osteosarcoma cells (1, 483 This article is freely accessible online.Correspondence to: Magdalena Gorska-Ponikowska (MGP),

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Section: Discussionmentioning

confidence: 99%

“…It was demonstrated that the induction of autophagy is associated with DNA damage (55)(56)(57). Autophagy has been shown to regulate some of the DNA repair proteins after DNA damage (55)(56)(57). One the other hand, some evidence has demonstrated that some DNA repair molecular have a crucial role in the initiation of autophagy (58,59).…”

Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Górska‐Ponikowska

Kuban–Jankowska

Daca

et al. 2017

CGP

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“…Global genotoxic damage induces genotoxin-induced targeted autophagy (GTA). GTA is a selective pathway of autophagy and requires the ATG11 gene (Eapen et al, 2017). Unlike the comprehensive studies in yeast, there are a few reports about the roles of ATG11-mediated selective autophagy in filamentous fungi.…”

Section: Introductionmentioning

confidence: 99%

Autophagy‐related gene BbATG11 is indispensable for pexophagy and mitophagy, and contributes to stress response, conidiation and virulence in the insect mycopathogen Beauveria bassiana

Ding

Peng

Chu

et al. 2018

Environmental Microbiology

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Autophagy is a conserved degradation system in eukaryotic cells that includes non-selective and selective processes. Selective autophagy functions as a selective degradation mechanism for specific substrates in which autophagy-related protein 11 (ATG11) acts as an essential scaffold protein. In B. bassiana, there is a unique ATG11 family protein, which is designated as BbATG11. Disruption of BbATG11 resulted in significantly reduced conidial germination under starvation stress. The mutant ΔBbATG11 displayed enhanced sensitivity to oxidative stress and impaired asexual reproduction. The conidial yield was reduced by approximately 75%, and this defective phenotype could be repressed by increasing exogenous nutrients. The virulence of the ΔBbATG11 mutant strain was significantly impaired as indicated in topical and intra-hemocoel injection bioassays, with a greater reduction in topical infection. Notably, BbATG11 was involved in pexophagy and mitophagy, but these two autophagic processes appeared in different fungal physiological aspects. Both pexophagy and mitophagy were associated with nutrient shift, starvation stress and growth in the host hemocoel, but only pexophagy appeared in both oxidation-stressed cells and aerial mycelia. This study highlights that BbATG11 mediates pexophagy and mitophagy in B. bassiana and links selective autophagy to the fungal stress response, conidiation and virulence.

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“…We have previously characterized an Mec1-and Tel1-dependent pathway for DNA damage-induced autophagy (22). We speculated that Pds1 is a target of GTA since we had shown Pds1 localized to vacuoles following a DSB.…”

Section: Pds1 Localizes To the Vacuole Independently Of Autophagymentioning

confidence: 98%

“…Both the localization and adaptation defects were rescued by deleting the vacuolar protease Pep4 (14), which is also required for the maturation of other resident vacuolar proteases (20,21). These observations along with the identification of a DNA damage-induced autophagy pathway termed, Genotoxin-induced Autophagy (GTA) (22), led us to suspect that Pds1 was a target of GTA. Here we show that Pds1 is targeted to the vacuole independently of autophagy and instead requires components of the alkaline phosphatase transport pathway (ALP) (23).…”

Section: Introductionmentioning

confidence: 99%

Yeast Securin is trafficked through the endomembrane system to regulate cell cycle arrest during the DNA damage response

Lemos¹,

Waterman²,

Haber³

2019

Preprint

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The yeast securin protein, Pds1, belongs to a class of highly conserved eukaryotic proteins that regulate the timing of chromatid segregation during mitosis by inhibiting separase, Esp1. During the metaphase to anaphase transition Pds1 is degraded by the ubiquitin-proteasome system in the nucleus, unleashing Esp1's protease activity to cleave cohesin surrounding sister chromatids. In response to DNA damage Pds1 is phosphorylated and stabilized, stalling mitotic progression to preserve genomic integrity. In addition, during the DNA damage checkpoint response, securin and separase are partially localized in the vacuole. Here we genetically dissect the requirements for securin's vacuolar localization and find that it is dependent on the Alkaline Phosphatase (ALP) endosomal transport pathway but not autophagy. Blocking retrograde traffic between the Golgi and the endoplasmic reticulum, by inhibiting COPI vesicle transport, drives Pds1 into the vacuole, whereas inhibiting antegrade transport by disrupting COPII-mediated traffic, results in the unexpected loss of Pds1 and the extinction of DNA damage-induced cell cycle arrest. We report that the induction of ER stress, either genetically or by treating cells with dithiothreitol, is sufficient to extinguish the DNA damage checkpoint, suggesting crosstalk between these two pathways. These data highlight new ways in which Pds1 and Esp1 are regulated during a DNA damage induced G2/M arrest and its requirement in the maintenance of the DNA damage checkpoint response.

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A pathway of targeted autophagy is induced by DNA damage in budding yeast

Cited by 57 publications

References 68 publications

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Autophagy‐related gene BbATG11 is indispensable for pexophagy and mitophagy, and contributes to stress response, conidiation and virulence in the insect mycopathogen Beauveria bassiana

Yeast Securin is trafficked through the endomembrane system to regulate cell cycle arrest during the DNA damage response

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