scholarly journals Expression of mammalian Onzin and Fungal Cadmium Resistance 1 in S. cerevisiae suggests ancestral functions of PLAC8 proteins in regulating mitochondrial metabolism and DNA damage repair

2018 ◽  
Author(s):  
Stefania Daghino ◽  
Luigi Di Vietro ◽  
Luca Petiti ◽  
Elena Martino ◽  
Cristina Dallabona ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Unknown Function ◽  
Protein Domains ◽  
Protein Domain ◽  
Specific Gene ◽  
Cadmium Resistance ◽  
Ancestral Function ◽  
Transcriptional Changes

AbstractProtein domains are structurally and functionally distinct units responsible for particular protein functions or interactions. Although protein domains contribute to the overall protein function(s) and can be used for protein classification, about 20% of protein domains are currently annotated as “domains of an unknown function” (DUFs). DUF 614, a cysteine-rich domain better known as PLAC8 (Placenta-Specific Gene 8), occurs in proteins found in the majority of Eukaryotes. PLAC8-containing 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. For example, Onzin from Mus musculus is a key regulator of cell proliferation, whereas FCR1 from the ascomycete Oidiodendron maius confers cadmium resistance. Onzin and FCR1 are small, single-domain PLAC8 proteins and we hypothesized that, despite their apparently different role, a common molecular function of these proteins may be linked to the PLAC8 domain. To address this hypothesis, we compared these two PLAC8-containing proteins by heterologous expression in the PLAC8-free yeast Saccharomyces cerevisiae. When expressed in yeast, both Onzin and FCR1 improved cadmium resistance, reduced cadmium-induced DNA mutagenesis, localized in the nucleus and induced similar transcriptional changes. Our results support the hypothesis of a common ancestral function of the PLAC8 domain that may link some mitochondrial biosynthetic pathways (i.e. leucine biosynthesis and Fe-S cluster biogenesis) with the control of DNA damage, thus opening new perspectives to understand the role of this protein domain in the cellular biology of Eukaryotes.Author SummaryProtein domains are the functional units of proteins and typically have distinct structure and function. However, many widely distributed protein domains are currently annotated as “domains of unknown function” (DUFs). We have focused on DUF 614, a protein domain found in many Eukaryotes and better known as PLAC8 (Placenta-Specific Gene 8). The functional role of DUF 614 is unclear because PLAC8 proteins seem to play important yet different roles in taxonomically distant organisms such as animals, plants and fungi. We used S. cerevisiae to test whether these apparently different functions, namely in cell proliferation and metal tolerance, respectively reported for the murine Onzin and the fungal FCR1, are mediated by the same molecular mechanisms. Our data demonstrate that the two PLAC8 proteins induced the same growth phenotype and transcriptional changes in S. cerevisiae. In particular, they both induced the biosynthesis of the amino acid leucine and of the iron-sulfur cluster, one of the most ancient protein cofactors. These similarities support the hypothesis of an ancestral function of the DUF 164 domain, whereas the transcriptomic data open new perspectives to understand the role of PLAC8-proteins in Eukaryotes.

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

2004 ◽  
Vol 287 (5) ◽  
pp. H1957-H1966 ◽  
Author(s):  
Faina Schwartz ◽  
Arvi Duka ◽  
Irena Duka ◽  
Jing Cui ◽  
Haralambos Gavras
Keyword(s):  
Gene Expression ◽  
Cardiac Remodeling ◽  
Unknown Function ◽  
Mouse Heart ◽  
Ang Ii ◽  
Coordinate Regulation ◽  
Transcriptional Changes ◽  
Novel Targets ◽  
Molecular Circuitry

Although the central role of ANG II in cardiovascular homeostasis is well appreciated, the molecular circuitry of its many actions is not completely understood. With the use of serial analysis of gene expression to assess global transcriptional changes in the heart of mice after continuous 7-day ANG II administration, we identified patterns of gene expression indicative of cardiac remodeling, including coordinate regulation of genes previously described in a context of processes associated with hypertrophy and fibrosis. In addition, we discovered several novel ANG II targets, including characterized genes of known function, recently annotated genes of unknown function, and the putative genes not yet present in current databases. The serial analysis of gene expression approach to assess the role of ANG II presented in this report provides new venues for inquiries into ANG II-mediated cardiac function.

scholarly journals Inferring Protein Domain Semantic Roles Using word2vec

2019 ◽  
Author(s):  
Daniel Buchan ◽  
David Jones
Keyword(s):  
Vector Space ◽  
Unknown Function ◽  
Protein Domains ◽  
Protein Domain ◽  
Semantic Meaning ◽  
Semantic Roles ◽  
Functional Roles ◽  
Eukaryotic Proteins

AbstractIn this paper, using word2vec, we demonstrate that proteins domains may have semantic “meaning” in the context of multi-domain proteins. Word2vec is a group of models which can be used to produce semantically meaningful embeddings of words or tokens in a vector space. In this work we treat multi-domain proteins as “sentences” where domain identifiers are tokens which may be considered as “words”. Using all Interpro (Finn, Attwood et al. 2017) eukaryotic proteins as a corpus of “sentences” we demonstrate that Word2vec creates functionally meaningful embeddings of protein domains. We additionally show how this can be applied to identifying the putative functional roles for Pfam (Finn, Coggill et al. 2016) Domains of Unknown Function.

scholarly journals Evolutionarily Conserved Role of Nucleostemin: Controlling Proliferation of Stem/Progenitor Cells during Early Vertebrate Development

2006 ◽  
Vol 26 (24) ◽  
pp. 9291-9301 ◽  
Author(s):  
Chantal Beekman ◽  
Massimo Nichane ◽  
Sarah De Clercq ◽  
Marion Maetens ◽  
Thomas Floss ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Embryonic Stem Cells ◽  
Progenitor Cells ◽  
Control Cell ◽  
Embryonic Stem ◽  
Physiological Role ◽  
Specific Gene

ABSTRACT Nucleostemin (NS) is a putative GTPase expressed preferentially in the nucleoli of neuronal and embryonic stem cells and several cancer cell lines. Transfection and knockdown studies indicated that NS controls the proliferation of these cells by interacting with the p53 tumor suppressor protein and regulating its activity. To assess the physiological role of NS in vivo, we generated a mutant mouse line with a specific gene trap event that inactivates the NS allele. The corresponding NS −/− embryos died around embryonic day 4. Analyses of NS mutant blastocysts indicated that NS is not required to maintain pluripotency, nucleolar integrity, or survival of the embryonic stem cells. However, the homozygous mutant blastocysts failed to enter S phase even in the absence of functional p53. Haploid insufficiency of NS in mouse embryonic fibroblasts leads to decreased cell proliferation. NS also functions in early amphibian development to control cell proliferation of neural progenitor cells. Our results show that NS has a unique ability, derived from an ancestral function, to control the proliferation rate of stem/progenitor cells in vivo independently of p53.

scholarly journals Identification of Essential Protein Domains From High-density Transposon Insertion Sequencing

2021 ◽  
Author(s):  
A.S.M. Zisanur Rahman ◽  
Lukas Timmerman ◽  
Flyn Gallardo ◽  
Silvia T. Cardona
Keyword(s):  
Unknown Function ◽  
Plant Pathogens ◽  
Bacterial Species ◽  
Protein Domains ◽  
Essential Genes ◽  
High Density ◽  
Protein Domain ◽  
Burkholderia Cenocepacia ◽  
Data Set ◽  
Essential Protein

Abstract A first clue to gene function can be obtained by examining whether a gene is required for life in certain standard conditions, that is, whether a gene is essential. In bacteria, essential genes are usually identified by high-density transposon mutagenesis followed by sequencing of insertion sites (Tn-seq). These studies assign the term “essential” to whole genes rather than the protein domain sequences that confer the essential functions. However, genes can code for multiple protein domains that evolve their functions independently. Therefore, when essential genes code for more than one protein domain, only one of them could be essential. In this study, we defined this subset of genes as “essential domain-containing” (EDC) genes. Using a Tn-seq data set built-in Burkholderia cenocepacia K56-2, we developed an in silico pipeline to identify EDC genes and the essential protein domains they encode. We found forty candidate EDC genes and demonstrated growth defect phenotypes using CRISPR interference (CRISPRi). This analysis included two knockdowns of genes encoding the protein domains of unknown function DUF2213 and DUF4148. These essential domains are conserved in more than two hundred bacterial species, including human and plant pathogens. Together, our study suggests that essentiality should be assigned to individual protein domains rather than genes, contributing to a first functional characterization of protein domains of unknown function.

scholarly journals Human core duplicon gene families: game changers or game players?

2019 ◽  
Vol 18 (6) ◽  
pp. 402-411 ◽  
Author(s):  
Cemalettin Bekpen ◽  
Diethard Tautz
Keyword(s):  
Positive Selection ◽  
Protein Domains ◽  
Gene Families ◽  
Specific Gene ◽  
Gene Duplications ◽  
Human Lineage ◽  
Protein Families ◽  
Cellular Pathways ◽  
Human Specific

Abstract Illuminating the role of specific gene duplications within the human lineage can provide insights into human-specific adaptations. The so-called human core duplicon gene families have received particular attention in this respect, due to special features, such as expansion along single chromosomes, newly acquired protein domains and signatures of positive selection. Here, we summarize the data available for 10 such families and include some new analyses. A picture emerges that suggests broad functions for these protein families, possibly through modification of core cellular pathways. Still, more dedicated studies are required to elucidate the function of core-duplicons gene families and how they have shaped adaptations and evolution of humans.

scholarly journals Role of Macrophages in Cytotoxicity, Reactive Oxygen Species Production and DNA Damage in 1,2-Dichloropropane-Exposed Human Cholangiocytes In Vitro

Toxics ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 128
Author(s):  
Abigail Ekuban ◽  
Cai Zong ◽  
Frederick Adams Ekuban ◽  
Yusuke Kimura ◽  
Ryoya Takizawa ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Cultured Cells ◽  
International Agency ◽  
Ros Production ◽  
Chlorinated Organic ◽  
Group 3 ◽  
Species Production

1,2-Dichloropropane (1,2-DCP), a synthetic chlorinated organic compound, was extensively used in the past in offset color proof-printing. In 2014, the International Agency for Research on Cancer (IARC) reclassified 1,2-DCP from its initial Group 3 to Group 1. Prior to the reclassification, cholangiocarcinoma was diagnosed in a group of workers exposed to 1,2 -DCP in an offset color proof-printing company in Japan. In comparison with other forms of cholangiocarcinoma, 1,2-DCP-induced cholangiocarcinoma was of early onset and accompanied by extensive pre-cancerous lesions in large bile ducts. However, the mechanism of 1,2-DCP-induced cholangiocarcinoma is poorly understood. Inflammatory cell proliferation was observed in various sites of the bile duct in the noncancerous hepatic tissues of the 1,2-DCP-induced cholangiocarcinoma. The aim of this study was to enhance our understanding of the mechanism of 1,2-DCP-related cholangiocarcinogenesis. We applied an in vitro system to investigate the effects of 1,2-DCP, using MMNK-1 cholangiocytes cultured alone or with THP-1 macrophages. The cultured cells were exposed to 1,2-DCP at 0, 0.1, 0.2, 0.4, and 0.8 mM for 24 h, and then assessed for cell proliferation, cell cytotoxicity, DNA damage, and ROS production. Exposure to 1,2-DCP increased proliferation of MMNK-1 cholangiocytes cultured alone, but not those cultured with macrophages. 1,2-DCP also increased LDH cytotoxicity, DNA damage, and ROS production in MMNK-1 cholangiocytes co-cultured with macrophages but not those cultured alone. 1,2-DCP increased TNFα and IL-1β protein expression in macrophages. The results highlight the role of macrophages in enhancing the effects of 1,2-DCP on cytotoxicity, ROS production, and DNA damage in cholangiocytes.

scholarly journals Phosphatidylinositol 5 Phosphate (PI5P): From Behind the Scenes to the Front (Nuclear) Stage

2019 ◽  
Vol 20 (9) ◽  
pp. 2080 ◽  
Author(s):  
Alessandro Poli ◽  
Antonio Enrico Zaurito ◽  
Shidqiyyah Abdul-Hamid ◽  
Roberta Fiume ◽  
Irene Faenza ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Chromatin Remodeling ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Cycles ◽  
The Core ◽  
Nuclear Stage ◽  
Cellular Compartments

Phosphatidylinositol (PI)-related signaling plays a pivotal role in many cellular aspects, including survival, cell proliferation, differentiation, DNA damage, and trafficking. PI is the core of a network of proteins represented by kinases, phosphatases, and lipases which are able to add, remove or hydrolyze PI, leading to different phosphoinositide products. Among the seven known phosphoinositides, phosphatidylinositol 5 phosphate (PI5P) was the last to be discovered. PI5P presence in cells is very low compared to other PIs. However, much evidence collected throughout the years has described the role of this mono-phosphoinositide in cell cycles, stress response, T-cell activation, and chromatin remodeling. Interestingly, PI5P has been found in different cellular compartments, including the nucleus. Here, we will review the nuclear role of PI5P, describing how it is synthesized and regulated, and how changes in the levels of this rare phosphoinositide can lead to different nuclear outputs.

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