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Tome, M.

Publications and source records attributed to Tome, M..

4 recordsLinked to original sources

GENOMIC ADAPTATION OF AN AUTOCHTHONOUS CIDER YEAST STRAIN TO BUCKWHEAT AND BARLEY WORT UNDER STRESSFUL BREWING CONDITIONS

Growing consumer demand for specialty beers with unique flavors and enhanced nutritional properties is driving the development of novel, high-performance industrial yeasts. However, the genetic diversity of beer yeast strains is limited. Traditional spontaneous fermentations are a rich source of new strains that are well adapted to fermentative environments but lack the ability to efficiently convert maltose-based substrates that are rich in polyphenols (e.g., buckwheat wort) or maltotriose-rich substrates (e.g., barley wort). To simulate the selection pressure exerted on beer yeasts during domestication, we used adaptive laboratory evolution (ALE) to yield cider yeast Saccharomyces cerevisiae that can efficiently convert buckwheat and barley wort into beer. To this end, 30 serial transfers of yeast biomass were conducted in high-pressure fermenters simulating industrial-scale stress conditions. This approach resulted in efficient maltose conversion in buckwheat wort and improved maltotriose conversion in barley wort. Three evolved clones from each evolutionary experiment were sequenced using short-read technology and aligned to the chromosome-level assembly of the ancestral cider strain. We observed pronounced genomic changes, including near-complete loss-of-heterozygosity, novel single-nucleotide mutations, and chromosomal aberrations resulting in altered chromosome copy numbers or segmental duplications. Additionally, the clones adapted to buckwheat wort were respiratory-deficient, either lacking or having impaired mitochondrial DNA, whereas clones adapted to barley wort retained a truncated mitochondrial genome. These genetic changes mirror hallmarks of beer yeast domestication and were also reflected phenotypically, including loss of sporulation capacity, decreased fitness under non-brewing conditions, and altered production of aromatic compounds. IMPORTANCEConsumer demand for specialty beers with distinctive flavors and nutritional value is growing and highlights the need for novel, high-performance beer yeasts adapted to stressful industrial conditions. This study demonstrates how adaptive laboratory evolution can be used to domesticate non-traditional yeasts, enabling efficient fermentation of alternative substrates, such as buckwheat and barley worts. The evolved strains not only improved sugar utilization under industrial conditions but also acquired genomic and phenotypic traits characteristic of domesticated beer yeasts. These findings demonstrate a viable strategy for expanding the functional diversity of brewing yeasts and support innovation in craft beer production.

microbiology↗

Asparagine endopeptidase promotes radioresistance in breast cancer through ATR pathway modulation

BackgroundTumor resistance represents a major challenge in the current oncology landscape. Asparagine endopeptidase (AEP) overexpression correlates with worse prognosis and reduced overall survival in most human solid tumors. However, the underlying mechanisms of the connection between AEP and reduced overall survival in cancer patients remain unclear. MethodsHigh-throughput proteomics, cellular and molecular biology approaches and clinical data from breast cancer (BC) patients were used to identify novel, biologically relevant AEP targets. Immunoblotting and qPCR analyses were used to quantify mRNA and protein levels. Flow cytometry, confocal microscopy, chemical inhibitors, siRNA- and shRNA-silencing and DNA repair assays were used as functional assays. In-silico analyses using the TCGA BC dataset and immunofluorescence assays in an independent cohort of invasive ductal (ID) BC patients were used to validate the clinical relevance of our findings. ResultsHere we showed a dual role for AEP in genomic stability and radiotherapy resistance in BC patients by suppressing ATR and PPP1R10 levels. Reduced ATR and PPP1R10 levels were found in BC patients expressing high AEP levels and correlated with worst prognosis. Mechanistically, AEP suppresses ATR levels, reducing DNA damage-induced cell death, and PPP1R10 levels, promoting Chek1/P53 cell cycle checkpoint activation, allowing BC cells to efficiently repair DNA. Functional studies revealed AEP-deficiency results in genomic instability, increased DNA damage signaling, reduced Chek1/P53 activation, impaired DNA repair and cell death, with phosphatase inhibitors restoring the DNA damage response in AEP-deficient BC cells. Furthermore, AEP inhibition sensitized BC cells to the chemotherapeutic reagents cisplatin and etoposide. Immunofluorescence assays in an independent cohort of IDBC patients showed increased AEP levels in ductal cells. These analyses showed that higher AEP levels in radioresistant IDBC patients result in ATR nuclear eviction, revealing AEPhigh/ATRlow protein levels as an efficient predictive biomarker for the stratification of radioresistant patients. ConclusionThe newly identified AEP/ATR/PPP1R10 axis plays a dual role in genomic stability and radiotherapy resistance in BC. Our work provides new clues to the underlying mechanisms of tumor resistance and strong evidence validating the AEP/ATR axis as a novel predictive biomarker and therapeutic target for the stratification and treatment of radioresistant BC patients.

cancer biology↗

FGFR1 inhibition prevents metabolic adaptation associated with therapy resistance in glioblastoma

Recurrent therapy resistance is a major limitation in clinical efficacy and for the outcome of glioblastoma (GBM) patients, positioning GBM among the tumor types with the poorest survival outcomes. In this work, we dissected resistance mechanisms in GBM, which resulted in the identification of FGFR1 pathway as a major regulator of the signaling and metabolic rewiring associated with temozolomide (TMZ) resistance in GBM. Hence, we described a mechanism of resistance that operates at two major levels. First, a p53-mediated regulation of cell cycle inducing cell cycle arrest to allow DNA repair in response to TMZ. And second, a complete metabolic rewiring promoting lipid catabolism and preventing lipid peroxidation. Both the p53-mediated response and the metabolic adaptation are controlled by FGFR1, as inhibition of the FGFR1 pathway completely abolishes this signaling and metabolic reprograming, restoring sensitivity to TMZ. Our results also indicated a correlation of FGFR1 levels with poor prognosis in GBM patients, and validated the treatment of TMZ in combination with FGFR1 inhibitors as an efficient strategy to induce tumor cell death in pre-clinical animal models. This data position the receptor FGFR1 as a very promising candidate for evaluation in future clinical approaches to limit the development of therapy resistance to TMZ in GBM patients.

cancer biology↗

Manganese is a Physiologically Relevant TORC1 Activator in Yeast and Mammals.

The essential biometal manganese (Mn) serves as a cofactor for several enzymes that are crucial for the prevention of human diseases. Whether intracellular Mn levels may be sensed and modulate intracellular signaling events has so far remained largely unexplored. The highly conserved target of rapamycin complex 1 (TORC1, mTORC1 in mammals) protein kinase requires divalent metal cofactors such as magnesium (Mg2+) to phosphorylate effectors as part of a homeostatic process that coordinates cell growth and metabolism with nutrient and/or growth factor availability. Here, our genetic approaches reveal that TORC1 activity is stimulated in vivo by elevated cytoplasmic Mn levels, which can be induced by loss of the Golgi-resident Mn2+ transporter Pmr1 and which depends on the natural resistance-associated macrophage protein (NRAMP) metal ion transporters Smf1 and Smf2. Accordingly, genetic interventions that increase cytoplasmic Mn2+ levels antagonize the effects of rapamycin in triggering autophagy, mitophagy, and Rtg1-Rtg3-dependent mitochondrion-to-nucleus retrograde signaling. Surprisingly, our in vitro protein kinase assays uncovered that Mn2+ activates TORC1 substantially better than Mg2+, which is primarily due to its ability to lower the Km for ATP, thereby allowing more efficient ATP coordination in the catalytic cleft of TORC1. These findings, therefore, provide both a mechanism to explain our genetic observations in yeast and a rationale for how fluctuations in trace amounts of Mn can become physiologically relevant. Supporting this notion, TORC1 is also wired to feedback control mechanisms that impinge on Smf1 and Smf2. Finally, we also show that Mn2+-mediated control of TORC1 is evolutionarily conserved in mammals, which may prove relevant for our understanding of the role of Mn in human diseases. Significance StatementThe target of rapamycin complex 1 (TORC1, mTORC1 in mammals) is a central, highly conserved controller of cell growth and aging in eukaryotes. Our study shows that the essential biometal manganese (Mn) acts as a primordial activator of TORC1 and that NRAMP metal ion transporters control TORC1 activity by regulating cytoplasmic Mn2+ levels. Moreover, TORC1 activity regulates Mn2+ levels through feedback circuits impinging on NRAMP transporters. Altogether, our results indicate that Mn homeostasis is highly regulated and modulates key cellular processes such as autophagy, mitophagy, and Rtg1-3 complex-dependent retrograde response. These findings open new perspectives for the understanding of neurodegenerative disorders and aging-related processes

cell biology↗