Publications by authors named "Angela Cirigliano"

12 Publications

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Active microbial ecosystem in Iron-Age tombs of the Etruscan civilization.

Environ Microbiol 2020 Nov 16. Epub 2020 Nov 16.

Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy.

Earth's microbial biosphere extends down through the crust and much of the subsurface, including those microbial ecosystems located within cave systems. Here, we elucidate the microbial ecosystems within anthropogenic 'caves'; the Iron-Age, subterranean tombs of central Italy. The interior walls of the rock (calcium-rich macco) were painted ~2500 years ago and are covered with CaCO needles (known as moonmilk). The aims of the current study were to: identify biological/geochemical/biophysical determinants of and characterize bacterial communities involved in CaCO precipitation; challenge the maxim that biogenic activity necessarily degrades surfaces; locate the bacterial cells that are the source of the CaCO precipitate; and gain insight into the kinetics of moonmilk formation. We reveal that this environment hosts communities that consist primarily of bacteria that are mesophilic for temperature and xerotolerance (including Actinobacteria, Bacteroidetes and Proteobacteria); is populated by photosynthetic Cyanobacteria exhibiting heterotrophic nutrition (Calothrix and Chroococcidiopsis); and has CaCO precipitating on the rock surfaces (confirmation that this process is biogenic) that acts to preserve rather than damage the painted surface. We also identified that some community members are psychrotolerant (Polaromonas), acidotolerant or acidophilic (members of the Acidobacteria), or resistant to ionizing radiation (Brevundimonas and Truepera); elucidate the ways in which microbiology impacts mineralogy and vice versa; and reveal that biogenic formation of moonmilk can occur rapidly, that is, over a period of 10 to 56 years. We discuss the paradox that these ecosystems, that are for the most part in the dark and lack primary production, are apparently highly active, biodiverse and biomass-rich.
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http://dx.doi.org/10.1111/1462-2920.15327DOI Listing
November 2020

Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1.

ACS Med Chem Lett 2020 May 10;11(5):1035-1040. Epub 2020 Apr 10.

Dipartimento di Biologia, Università di Padova Distaccato presso il "Centro Linceo Beniamino Segre" Accademia Nazionale dei Lincei, Palazzo Corsini, Via della Lungara 10, 00165 Rome, Italy.

Artesunic acid and artemisinin are natural substances with promiscuous anticancer activity against different types of cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested topoisomerase 1 as a possible molecular target for the improvement of the anticancer activity of these compounds. In this context, we report that novel hybrid and dimer derivatives of artesunic acid and artemisinin, bearing camptothecin and SN38 as side-chain biological effectors, can inhibit growth of yeast cells overexpressing human topoisomerase 1 and its enzymatic activity . These derivatives showed also anticancer activity in melanoma cell lines higher than camptothecin and paclitaxel. molecular docking calculations highlighted a common binding mode for the novel derivatives, with the sesquiterpene lactone scaffold being located near the traditional recognition site for camptothecin, while the bioactive side-chain effector laid in the camptothecin cleft.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236541PMC
May 2020

The COP9 signalosome mediates the Spt23 regulated fatty acid desaturation and ergosterol biosynthesis.

FASEB J 2020 04 19;34(4):4870-4889. Epub 2020 Feb 19.

Department of Biology and Environment, Faculty of Natural Sciences, University of Haifa, Oranim, Israel.

The COP9 signalosome (CSN) is a conserved eukaryotic complex, essential for vitality in all multicellular organisms and critical for the turnover of key cellular proteins through catalytic and non-catalytic activities. Saccharomyces cerevisiae is a powerful model organism for studying fundamental aspects of the CSN complex, since it includes a conserved enzymatic core but lacks non-catalytic activities, probably explaining its non-essentiality for life. A previous transcriptomic analysis of an S. cerevisiae strain deleted in the CSN5/RRI1 gene, encoding to the CSN catalytic subunit, revealed a downregulation of genes involved in lipid metabolism. We now show that the S. cerevisiae CSN holocomplex is essential for cellular lipid homeostasis. Defects in CSN assembly or activity lead to decreased quantities of ergosterol and unsaturated fatty acids (UFA); vacuole defects; diminished lipid droplets (LDs) size; and to accumulation of endoplasmic reticulum (ER) stress. The molecular mechanism behind these findings depends on CSN involvement in upregulating mRNA expression of SPT23. Spt23 is a novel activator of lipid desaturation and ergosterol biosynthesis. Our data reveal for the first time a functional link between the CSN holocomplex and Spt23. Moreover, CSN-dependent upregulation of SPT23 transcription is necessary for the fine-tuning of lipid homeostasis and for cellular health.
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http://dx.doi.org/10.1096/fj.201902487RDOI Listing
April 2020

Statins interfere with the attachment of mtDNA to the inner mitochondrial membrane.

J Enzyme Inhib Med Chem 2020 Dec;35(1):129-137

Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy.

The 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme of the mevalonate pathway for the synthesis of cholesterol in mammals (ergosterol in fungi), is inhibited by statins, a class of cholesterol lowering drugs. Indeed, statins are in a wide medical use, yet statins treatment could induce side effects as hepatotoxicity and myopathy in patients. We used as a model to investigate the effects of statins on mitochondria. We demonstrate that statins are active in by lowering the ergosterol content in cells and interfering with the attachment of mitochondrial DNA to the inner mitochondrial membrane. Experiments on murine myoblasts confirmed these results in mammals. We propose that the instability of mitochondrial DNA is an early indirect target of statins.
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http://dx.doi.org/10.1080/14756366.2019.1687461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844431PMC
December 2020

The Proteasome Lid Triggers COP9 Signalosome Activity during the Transition of Cells into Quiescence.

Biomolecules 2019 09 4;9(9). Epub 2019 Sep 4.

Department of Biology and Environment, Faculty of Natural Sciences, University of Haifa at Oranim, Tivon 36006, Israel.

The class of Cullin-RING E3 ligases (CRLs) selectively ubiquitinate a large portion of proteins targeted for proteolysis by the 26S proteasome. Before degradation, ubiquitin molecules are removed from their conjugated proteins by deubiquitinating enzymes, a handful of which are associated with the proteasome. The CRL activity is triggered by modification of the Cullin subunit with the ubiquitin-like protein, NEDD8 (also known as Rub1 in ). Cullin modification is then reversed by hydrolytic action of the COP9 signalosome (CSN). As the NEDD8-Rub1 catalytic cycle is not essential for the viability of , this organism is a useful model system to study the alteration of Rub1-CRL conjugation patterns. In this study, we describe two distinct mutants of Rpn11, a proteasome-associated deubiquitinating enzyme, both of which exhibit a biochemical phenotype characterized by high accumulation of Rub1-modified Cdc53-Cullin1 (yCul1) upon entry into quiescence in . Further characterization revealed proteasome 19S-lid-associated deubiquitination activity that authorizes the hydrolysis of Rub1 from yCul1 by the CSN complex. Thus, our results suggest a negative feedback mechanism via proteasome capacity on upstream ubiquitinating enzymes.
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http://dx.doi.org/10.3390/biom9090449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770237PMC
September 2019

Ergosterol reduction impairs mitochondrial DNA maintenance in S. cerevisiae.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 03 12;1864(3):290-303. Epub 2018 Dec 12.

Department of Biology and Biotechnology "Charles Darwin", La Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy.; Pasteur Institute-Cenci Bolognetti Foundation, Viale Regina Elena, 291, 00100 Rome, Italy.. Electronic address:

Sterols are essential lipids, involved in many biological processes. In Saccharomyces cerevisiae, the enzymes of the ergosterol biosynthetic pathway (Erg proteins) are localized in different cellular compartments. With the aim of studying organelle interactions, we discovered that Erg27p resides mainly in Lipid Droplets (LDs) in respiratory competent cells, while in absence of respiration, is found mostly in the ER. The results presented in this paper demonstrate an interplay between the mitochondrial respiration and ergosterol production: on the one hand, rho° cells show lower ergosterol content when compared with wild type respiratory competent cells, on the other hand, the ergosterol biosynthetic pathway influences the mitochondrial status, since treatment with ketoconazole, which blocks the ergosterol pathway, or the absence of the ERG27 gene, induced rho° production in S. cerevisiae. The loss of mitochondrial DNA in the ∆erg27 strain is fully suppressed by exogenous addition of ergosterol. These data suggest the notion that ergosterol is essential for maintaining the mitochondrial DNA attached to the inner mitochondrial membrane.
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http://dx.doi.org/10.1016/j.bbalip.2018.12.002DOI Listing
March 2019

Calcite moonmilk of microbial origin in the Etruscan Tomba degli Scudi in Tarquinia, Italy.

Sci Rep 2018 10 26;8(1):15839. Epub 2018 Oct 26.

La Sapienza University of Rome, Dept. of Biology and Biotechnology Charles Darwin, Rome, 00185, Italy.

A white deposit covering the walls in the Stanza degli Scudi of the Tomba degli Scudi, Tarquinia, Italy, has been investigated. In this chamber, which is still preserved from any kind of intervention such as cleaning and sanitization, ancient Etruscans painted shields to celebrate the military power of the Velcha family. Scanning electron microscopy analysis has revealed the presence of characteristic nanostructures corresponding to a calcite secondary mineral deposit called moonmilk. Analysis of the microbial community identified Proteobacteria, Acidobacteria and Actinobacteria as the most common phyla in strong association with the moonmilk needle fibre calcite and nanofibers of calcium carbonate. Employing classical microbiological analysis, we isolated from moonmilk a Streptomyces strain able to deposit gypsum and calcium carbonate on plates, supporting the hypothesis of an essential contribution of microorganisms to the formation of moonmilk.
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http://dx.doi.org/10.1038/s41598-018-34134-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203712PMC
October 2018

A role for microbial selection in frescoes' deterioration in Tomba degli Scudi in Tarquinia, Italy.

Sci Rep 2017 07 20;7(1):6027. Epub 2017 Jul 20.

La Sapienza University of Rome, Departement of Biology and Biotechnology "Charles Darwin", Piazzale Aldo Moro, 5, 00185, Rome, Italy.

Mural paintings in the hypogeal environment of the Tomba degli Scudi in Tarquinia, Italy, show a quite dramatic condition: the plaster mortar lost his cohesion and a white layer coating is spread over almost all the wall surfaces. The aim of this research is to verify if the activity of microorganisms could be one of the main causes of deterioration and if the adopted countermeasures (conventional biocide treatments) are sufficient to stop it. A biocide treatment of the whole environment has been carried out before the conservative intervention and the tomb has been closed for one month. When the tomb was opened again, we sampled the microorganisms present on the frescoes and we identified four Bacillus species and one mould survived to the biocide treatment. These organisms are able to produce spores, a highly resistant biological form, which has permitted the survival despite the biocide treatment. We show that these Bacillus strains are able to produce calcium carbonate and could be responsible for the white deposition that was damaging and covering the entire surface of the frescoes. Our results confirm that the sanitation intervention is non always resolutive and could even be deleterious in selecting harmful microbial communities.
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http://dx.doi.org/10.1038/s41598-017-06169-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519700PMC
July 2017

Biological Dual-Use Research and Synthetic Biology of Yeast.

Sci Eng Ethics 2017 04 20;23(2):365-374. Epub 2016 Jun 20.

Department of Biology and Biotechnology, La Sapienza University of Rome, Rome, Italy.

In recent years, the publication of the studies on the transmissibility in mammals of the H5N1 influenza virus and synthetic genomes has triggered heated and concerned debate within the community of scientists on biological dual-use research; these papers have raised the awareness that, in some cases, fundamental research could be directed to harmful experiments, with the purpose of developing a weapon that could be used by a bioterrorist. Here is presented an overview regarding the dual-use concept and its related international agreements which underlines the work of the Australia Group (AG) Export Control Regime. It is hoped that the principles and activities of the AG, that focuses on export control of chemical and biological dual-use materials, will spread and become well known to academic researchers in different countries, as they exchange biological materials (i.e. plasmids, strains, antibodies, nucleic acids) and scientific papers. To this extent, and with the aim of drawing the attention of the scientific community that works with yeast to the so called Dual-Use Research of Concern, this article reports case studies on biological dual-use research and discusses a synthetic biology applied to the yeast Saccharomyces cerevisiae, namely the construction of the first eukaryotic synthetic chromosome of yeast and the use of yeast cells as a factory to produce opiates. Since this organism is considered harmless and is not included in any list of biological agents, yeast researchers should take simple actions in the future to avoid the sharing of strains and advanced technology with suspicious individuals.
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http://dx.doi.org/10.1007/s11948-016-9774-1DOI Listing
April 2017

Functional roles of the fatty acid desaturases encoded by KlOLE1, FAD2 and FAD3 in the yeast Kluyveromyces lactis.

Microbiology (Reading) 2016 08 27;162(8):1435-1445. Epub 2016 May 27.

Department of Biology and Biotechnology C. Darwin, Sapienza Università di Roma, p.le Aldo Moro 5, 00185, Roma, Italy.

Functional properties of cell membranes depend on their composition, particularly on the relative amount of saturated, unsaturated and polyunsaturated fatty acids present in the phospholipids. The aim of this study was to investigate the effect of cell membrane composition on cell fitness, adaptation and stress response in Kluyveromyces lactis. To this purpose, we have deleted the genes FAD2 and FAD3 encoding Δ12 and ω3 desaturases in Kluyveromyces lactis, thus generating mutant strains with altered fatty acid composition of membranes. These strains were viable and able to grow in stressing conditions like hypoxia and low temperature. Deletion of the Δ9 desaturase-encoding gene KlOLE1 resulted in lethality, suggesting that this enzyme has an essential role in this yeast. Transcription of the desaturase genes KlOLE1, FAD2 and FAD3 and cellular localization of the corresponding enzymes, have been studied under hypoxia and cold stress. Our findings indicate that expression of these desaturase genes and membrane composition were modulated by hypoxia and temperature stress, although the changes induced by these and other assayed conditions did not dramatically affect the general cellular fitness.
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http://dx.doi.org/10.1099/mic.0.000315DOI Listing
August 2016

Yeast as a tool to select inhibitors of the cullin deneddylating enzyme Csn5.

J Enzyme Inhib Med Chem 2016 Dec 30;31(6):1632-7. Epub 2016 Mar 30.

a Istituto Pasteur Fondazione Cenci Bolognetti, Department of Biology and Biotechnology, Sapienza University of Rome , Rome , Italy .

The CSN complex plays a key role in various cellular pathways: through a metalloprotease activity of its Csn5 deneddylating enzyme, it regulates the activity of Cullin-RING ligases (CRLs). Indeed, Csn5 has been found amplified in many tumors, but, due to its pleiotropic effects, it is difficult to dissect its function and the involvement in cancer progression. Moreover, while growing evidences point to the neddylation function as a good target for drug development; specific inhibitors have not yet been developed for the CSN. Here, we propose the yeast Saccharomyces cerevisiae as a model system to screen libraries of small molecules as inhibitors of cullins deneddylation, taking advantage of the unique feature of this organism to survive without a functional CSN5 gene and to accumulate a fully neddylated cullin substrate. By combining molecular modeling and simple genetic tools, we were able to identify two small molecular fragments as selective inhibitors of Csn5 deneddylation function.
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http://dx.doi.org/10.3109/14756366.2016.1160901DOI Listing
December 2016

The human SLC25A33 and SLC25A36 genes of solute carrier family 25 encode two mitochondrial pyrimidine nucleotide transporters.

J Biol Chem 2014 Nov 15;289(48):33137-48. Epub 2014 Oct 15.

From the Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, via Orabona 4, 70125 Bari, Italy, Center of Excellence in Comparative Genomics, University of Bari, via Orabona 4, 70125 Bari, Italy

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport inorganic anions, amino acids, carboxylates, nucleotides, and coenzymes across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. Here two members of this family, SLC25A33 and SLC25A36, have been thoroughly characterized biochemically. These proteins were overexpressed in bacteria and reconstituted in phospholipid vesicles. Their transport properties and kinetic parameters demonstrate that SLC25A33 transports uracil, thymine, and cytosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism and SLC25A36 cytosine and uracil (deoxy)nucleoside mono-, di-, and triphosphates by uniport and antiport. Both carriers also transported guanine but not adenine (deoxy)nucleotides. Transport catalyzed by both carriers was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. In confirmation of their identity (i) SLC25A33 and SLC25A36 were found to be targeted to mitochondria and (ii) the phenotypes of Saccharomyces cerevisiae cells lacking RIM2, the gene encoding the well characterized yeast mitochondrial pyrimidine nucleotide carrier, were overcome by expressing SLC25A33 or SLC25A36 in these cells. The main physiological role of SLC25A33 and SLC25A36 is to import/export pyrimidine nucleotides into and from mitochondria, i.e. to accomplish transport steps essential for mitochondrial DNA and RNA synthesis and breakdown.
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http://dx.doi.org/10.1074/jbc.M114.610808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246075PMC
November 2014
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