Increased levels of RNA oxidation enhance the reversion frequency in aging pro-apoptotic yeast mutants.
Despite recent advances in understanding the complexity of RNA processes, regulation of the metabolism of oxidized cellular RNAs and the mechanisms through which oxidized ribonucleotides affect mRNA translation, and consequently cell viability, are not well characterized. We show here that the level of oxidized RNAs is markedly increased in a yeast decapping Kllsm4Δ1 mutant, which accumulates mRNAs, ages much faster that the wild type strain and undergoes regulated-cell-death. We also found that in Kllsm4Δ1 cells the mutation rate increases during chronological life span indicating that the capacity to handle oxidized RNAs in yeast declines with aging. Lowering intracellular ROS levels by antioxidants recovers the wild-type phenotype of mutant cells, including reduced amount of oxidized RNAs and lower mutation rate. Since mRNA oxidation was reported to occur in different neurodegenerative diseases, decapping-deficient cells may represent a useful tool for deciphering molecular mechanisms of cell response to such conditions, providing new insights into RNA modification-based pathogenesis.
Department of Biology and Biotechnology "Charles Darwin", Istituto Pasteur Italia-Fondazione Cenci Bolognetti, University "Sapienza" of Rome, Piazzale Aldo Moro 5, Rome, Italy.
Mariarita
M
Stirpe
Department of Biology and Biotechnology "Charles Darwin", Istituto Pasteur Italia-Fondazione Cenci Bolognetti, University "Sapienza" of Rome, Piazzale Aldo Moro 5, Rome, Italy.
Vanessa
V
Palermo
Department of Biology and Biotechnology "Charles Darwin", Istituto Pasteur Italia-Fondazione Cenci Bolognetti, University "Sapienza" of Rome, Piazzale Aldo Moro 5, Rome, Italy.
Matteo
M
Ferrari
Faculty of Biology, Institute of Genetics and Biotechnology, University of Warsaw, Pawinskiego 5a, 02-106, Warsaw, Poland.
Seweryn
S
Mroczek
Faculty of Biology, Institute of Genetics and Biotechnology, University of Warsaw, Pawinskiego 5a, 02-106, Warsaw, Poland.
Joanna
J
Kufel
Department of Biology and Biotechnology "Charles Darwin", Istituto Pasteur Italia-Fondazione Cenci Bolognetti, University "Sapienza" of Rome, Piazzale Aldo Moro 5, Rome, Italy.
Claudio
C
Falcone
Department of Biology and Biotechnology "Charles Darwin", Istituto Pasteur Italia-Fondazione Cenci Bolognetti, University "Sapienza" of Rome, Piazzale Aldo Moro 5, Rome, Italy. cristina.mazzoni@uniroma1.it.
Cristina
http://orcid.org/0000-0002-1504-6189
C
Mazzoni
D000375:Aging / Q000235:genetics* / Q000473:pathology; D017209:Apoptosis / Q000235:genetics*; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D017382:Reactive Oxygen Species
Apoptosis; Genomic instability; Mutation frequency; Oxidative stress; RNA degradation; Yeast