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Yeast expression of mammalian Onzin and fungal FCR1 suggests ancestral functions of PLAC8 proteins in mitochondrial metabolism and DNA repair

Abstract : The cysteine-rich PLAC8 domain of unknown function occurs in proteins found in most Eukaryotes. PLAC8-proteins play important yet diverse roles in different organisms, such as control of cell proliferation in animals and plants or heavy metal resistance in plants and fungi. Mammalian Onzin can be either pro-proliferative or pro-apoptotic, depending on the cell type, whereas fungal FCR1 confers cadmium tolerance. Despite their different role in different organisms, we hypothesized common ancestral functions linked to the PLAC8 domain. To address this hypothesis, and to investigate the molecular function of the PLAC8 domain, murine Onzin and fungal FCR1 were expressed in the PLAC8-free yeast Saccharomyces cerevisiae. The two PLAC8-proteins localized in the nucleus and induced almost identical phenotypes and transcriptional changes when exposed to cadmium stress. Like FCR1, Onzin also reduced DNA damage and increased cadmium tolerance by a DUN1-dependent pathway. Both proteins activated transcription of ancient mitochondrial pathways such as leucine and Fe-S cluster biosynthesis, known to regulate cell proliferation and DNA repair in yeast. These results strongly suggest a common ancestral function of PLAC8 proteins and open new perspectives to understand the role of the PLAC8 domain in the cellular biology of Eukaryotes. The PLAC8 domain was described for the first time in the protein Onzin, the product of the human Placenta-Specific Gene 8 1. The same domain was later identified in many Eukaryotes, but its biological role remains elusive because PLAC8 proteins seem to play diverse roles in different organisms and cell types. The mammalian Onzin has been reported as a repressed target of the c-Myc oncoprotein 2 , with pro-proliferative anti-apoptotic effects in many cell types and a role in leukemia 3 , hepatic, pancreatic 4,5 and colon cancer progression 6,7 , but also in adipocyte growth 8. The same protein has pro-apoptotic activity in other cell types 9 , indicating that the final effect of Onzin is highly dependent on cell type. In plants, PLAC8 genes are also involved in cell proliferation because mutants are altered in organs size. The tomato Fruit Weight 2.2 (FW2.2) negatively influences fruit size and is downregulated in domesticated species 10. Similar function has been reported for FW2.2-like genes in other plant species, both dicots 11-14 and monocots 15,16. Another cellular role of PLAC8 proteins in plants and fungi is to increase resistance to heavy metals. First described in Arabidopsis thaliana, the Plant Cadmium Resistance (PCR) protein family includes proteins that confer resistance to cadmium or zinc. AtPCR1 was suggested to be-or to be part of-a cadmium transporter because of its localization on the plasma membrane in both A. thaliana and S. cerevisiae 17 , while AtPCR2 was associated to zinc transport 18. Although PLAC8 domain containing genes have been annotated in many fungal
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Stefania Daghino, Luigi Di Vietro, Luca Petiti, Elena Martino, Cristina Dallabona, et al.. Yeast expression of mammalian Onzin and fungal FCR1 suggests ancestral functions of PLAC8 proteins in mitochondrial metabolism and DNA repair. Scientific Reports, 2019, 9 (6629), ⟨10.1038/s41598-019-43136-3⟩. ⟨hal-02948853⟩

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