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Characterization of unknown function ORFs involved in Saccharomyces cerevisiae antioxidant response

Grant number: 09/01303-1
Support type:Research Grants - Young Investigators Grants
Duration: August 01, 2009 - July 31, 2014
Field of knowledge:Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
Principal researcher:Gisele Monteiro
Grantee:Gisele Monteiro
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):13/08139-8 - Cloning, expression and charactherization of L-asparaginases from Saccharomyces cerevisiae and comparison with bacterial L-asparaginases used to treat Leukemia., BP.IC
11/05156-3 - Study of the biological function of the Alternative Oxidase (AOX) from Moniliophthora pernciosa (witches' broom fungus) using Saccharomyces cerevisiae., BP.MS
11/04938-8 - Identification of molecular targets associated to gemcitabine and rebeccamycin analogues resistance using Saccharomyces cerevisiae as model cell, BP.MS
+ associated scholarships 11/04173-1 - Identification of molecular targets asscociated with resistance to antitumor drugs Carboplatin and Rebeccamycin analogues using Saccharomyces cerevisiae as model cell, BP.MS
10/08592-6 - Study of the YDL118W biological function - ORF of unknown function - involvement in the genome maintenance and stability and its relationship with oxidative stress in Saccharomyces cerevisiae., BP.IC
09/10729-2 - YMR134W essential ORF of unknown function characterization - involvement in the antioxiddant response and iron metabolism in Saccharomyces cerevisiae., BP.IC - associated scholarships

Abstract

There are approximately 800 sequenced genomes and only 40% of the sequences are annotated as gene with biological known function. Saccharomyces cerevisiae is one of the most well studied model organism, however, around 20% of its ORFs (open reading frames) possess no structure and/or molecular function determined. So, the aim of the present project is to characterize some of these ORFs which are involved in the antioxidant response. The project is relevant in the cellular redox regulation area since it searches by new pathways and mediators to the process. All the time we are exposed to reactive oxygen species produced as byproducts of respiratory chain. Besides, UV radiation, pollution and several other environmental factors increase the pro-oxidant species formation which, in excess, results in oxidative stress. The oxidative stress is known by cause damages in biomolecules such as DNA, protein and lipids. To defend our cells against these damages we possess a complex antioxidant system, being several of its components with poorly known biological function. Recently, a lot of information has been produced about antioxidant properties of enzymes and low molecular weight compounds. The description of sulfiredoxin resulted in a paradigm break about the overoxidized state of proteic cysteines, becoming an example of protein repair enzyme such as methionine sulfoxide reductase (described in the 80´s decade). The vitamin C which was known as oxidant species neutralizing agent gained status of double action: acting also in the prevention of free radicals formation since it regenerates antioxidant enzymes responsible for neutralizing the pro oxidants (for example peroxides; Monteiro et al., PNAS, 2007). The pro oxidants role, in turn, has been gained importance in the comprehension of cellular biology with the classic example of nitric oxide. The description of the signaling pathways mediated by this free radical (also described in 80´s decade) lead to discover of new drugs and resulted in significant improvement in life quality of many people. These are examples of the importance of redox mechanisms studies, since important mediators of the process have been yet described. After more than 10 years that Saccharomyces cerevisiae genome was completely sequenced, around 1200 possible proteins are uncharacterized. Through our studies we would be able to describe new metabolic pathways, new mediators as important as nitric oxide and, maybe, they result in benefits and knowledge about cellular biology. The project also opens the possibility of several research collaborations; the yeast collection separated for this project allows the analyses of different phenotypes involved in basic cellular biology mechanisms of interest of other research group. We will analyze the viability of a mutant yeast collection, carry out complementation assay and individual gene expression studies to determine the biological function. We will clone, express and purify the target proteins to test activity and to determine tertiary structure allowing comparisons with other known proteins, to understand the biochemical and molecular function. The antioxidant response is related with several human pathologic processes such as neurodegenerative diseases, aging, inflammation, ischemia- reperfusion, among others. Besides, yeast metabolism and physiology comprehension may result in direct implications to biotechnology since S. cerevisiae is largely used in fermentation processes (ethanol, wine, bread, beer) and to heterologous protein production with commercial and industrial interest. (AU)

Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CAVALCANTE, LUCAS DE SOUSA; COSTA-SILVA, TALES A.; SOUZA, TIAGO ANTONIO; IENNE, SUSAN; MONTEIRO, GISELE. Chemogenomic study of gemcitabine using Saccharomyces cerevisiae as model cell-molecular insights about chemoresistance. Brazilian Journal of Microbiology, v. 51, n. 2, p. 489-496, JUN 2020. Web of Science Citations: 0.
MORETTI-ALMEIDA, G.; THOMAZELLA, D. P. T.; PEREIRA, G. A. G.; MONTEIRO, G. Heterologous expression of an alternative oxidase from Moniliophthora perniciosa in Saccharomyces cerevisiae: Antioxidant function and in vivo platform for the study of new drugs against witches' broom disease. Fungal Genetics and Biology, v. 126, p. 50-55, MAY 2019. Web of Science Citations: 1.
DE SOUSA, GRAZIELE FONSECA; LIMA, MAIRA DE ASSIS; CUSTODIO, DEBORA FERNANDES; FREITAS, VANESSA MORAIS; MONTEIRO, GISELE. Chemogenomic Study of Carboplatin in Saccharomyces cerevisiae: Inhibition of the NEDDylation Process Overcomes Cellular Resistance Mediated by HuR and Cullin Proteins. PLoS One, v. 10, n. 12 DEC 21 2015. Web of Science Citations: 9.
ALESSO, C. A.; DISCOLA, K. F.; MONTEIRO, G. The gene ICS3 from the yeast Saccharomyces cerevisiae is involved in copper homeostasis dependent on extracellular pH. Fungal Genetics and Biology, v. 82, p. 43-50, SEP 2015. Web of Science Citations: 0.
CAVALCANTE, LUCAS DE SOUSA; MONTEIRO, GISELE. Gemcitabine: Metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. European Journal of Pharmacology, v. 741, p. 8-16, OCT 15 2014. Web of Science Citations: 152.
DE SOUSA, GRAZIELE FONSECA; WLODARCZYK, SAMARINA RODRIGUES; MONTEIRO, GISELE. Carboplatin: molecular mechanisms of action associated with chemoresistance. Brazilian Journal of Pharmaceutical Sciences, v. 50, n. 4, p. 693-701, OCT-DEC 2014. Web of Science Citations: 14.

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