Fundación Instituto Leloir

About: Fundación Instituto Leloir is a facility organization based out in Buenos Aires, Argentina. It is known for research contribution in the topics: Dentate gyrus & Neurogenesis. The organization has 702 authors who have published 1052 publications receiving 39299 citations.

Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities.

Abstract: Chromosomal instability (CIN) refers to an increased rate of acquisition of numerical and structural changes in chromosomes and is considered an enabling characteristic of tumors. Given its role as a facilitator of genomic changes, CIN is increasingly being considered as a possible therapeutic target, raising the question of which variables may convert CIN into an ally instead of an enemy during cancer treatment. This review discusses the origins of structural chromosome abnormalities and the cellular mechanisms that prevent and resolve them, as well as how different CIN phenotypes relate to each other. We discuss the possible fates of cells containing structural CIN, focusing on how a few cell duplication cycles suffice to induce profound CIN-mediated genome alterations. Because such alterations can promote tumor adaptation to treatment, we discuss currently proposed strategies to either avoid CIN or enhance CIN to a level that is no longer compatible with cell survival.

Mus81-Eme1-dependent aberrant processing of DNA replication intermediates in mitosis impairs genome integrity.

Abstract: Chromosome instability (CIN) underpins cancer evolution and is associated with drug resistance and poor prognosis. Understanding the mechanistic basis of CIN is thus a priority. The structure-specific endonuclease Mus81-Eme1 is known to prevent CIN. Intriguingly, however, here we show that the aberrant processing of late replication intermediates by Mus81-Eme1 is a source of CIN. Upon depletion of checkpoint kinase 1 (Chk1), Mus81-Eme1 cleaves under-replicated DNA engaged in mitotic DNA synthesis, leading to chromosome segregation defects. Supplementing cells with nucleosides allows the completion of mitotic DNA synthesis, restraining Mus81-Eme1-dependent DNA damage in mitosis and the ensuing CIN. We found no correlation between CIN arising from nucleotide shortage in mitosis and cell death, which were selectively linked to DNA damage load in mitosis and S phase, respectively. Our findings imply the possibility of optimizing Chk1-directed therapies by inducing cell death while curtailing CIN, a common side effect of chemotherapy.

Lipopolysaccharide O-chain core region required for cellular cohesion and compaction of in vitro and root biofilms developed by Rhizobium leguminosarum.

Abstract: The formation of biofilms is an important survival strategy allowing rhizobia to live on soil particles and plant roots. Within the microcolonies of the biofilm developed by Rhizobium leguminosarum, rhizobial cells interact tightly through lateral and polar connections, forming organized and compact cell aggregates. These microcolonies are embedded in a biofilm matrix, whose main component is the acidic exopolysaccharide (EPS). Our work shows that the O-chain core region of the R. leguminosarum lipopolysaccharide (LPS) (which stretches out of the cell surface) strongly influences bacterial adhesive properties and cell-cell cohesion. Mutants defective in the O chain or O-chain core moiety developed premature microcolonies in which lateral bacterial contacts were greatly reduced. Furthermore, cell-cell interactions within the microcolonies of the LPS mutants were mediated mostly through their poles, resulting in a biofilm with an altered three-dimensional structure and increased thickness. In addition, on the root epidermis and on root hairs, O-antigen core-defective strains showed altered biofilm patterns with the typical microcolony compaction impaired. Taken together, these results indicate that the surface-exposed moiety of the LPS is crucial for proper cell-to-cell interactions and for the formation of robust biofilms on different surfaces.

Characterization of UDP-glucose:protein transglucosylase genes from potato.

Abstract: Many plant autocatalytic glycosyltransferases are implicated in plant polysaccharide biosynthesis. Cloning of cDNAs encoding potato (Solanum tuberosum L.) UDP-Glc:protein transglucosylase (UPTG, EC 2.4.1.112) and expression of the cDNA clone E11 in Escherichia coli have been previously reported. Here, we studied the functional expression of a second cDNA of the enzyme (E2 clone). Northern blots analysis, with specific cDNA probes for the two UPTG isoforms, showed a differential expression pattern of mRNA levels in different potato tissues. Moreover, both UPTG recombinant enzymes showed different kinetic parameters. The recombinant protein encoded by E2 clone has an apparent Imax for UDP-Xyl and UDP-Gal, significantly higher than for UDP-Glc. The Km values for UDP-Glc were 0.45–0.71 µM and the values for UDP-Xyl and UDP-Gal were slightly higher than that of the UDP-Glc (1.2–2.71 µM) for both UPTG recombinant enzymes. The present study revealed further evidence for the proposed role of UPTG in the synthesis of cell wall polysaccharide. It was found a correlation between UPTG transcript levels and the growing state of the tissues in which there was an active synthesis of cell wall components. Southern blot analysis indicates that at least three genes encoding UPTG are present in potato genome. Phylogenetic analysis of both UPTG recombinant proteins showed that they are members of the RGP subfamilies from dicots.

SPARC (secreted protein acidic and rich in cysteine) knockdown protects mice from acute liver injury by reducing vascular endothelial cell damage.

Abstract: Secreted protein, acidic and rich in cysteine (SPARC) is involved in many biological process including liver fibrogenesis, but its role in acute liver damage is unknown. To examine the role of SPARC in acute liver injury, we used SPARC knock-out (SPARC−/−) mice. Two models of acute liver damage were used: concanavalin A (Con A) and the agonistic anti-CD95 antibody Jo2. SPARC expression levels were analyzed in liver samples from patients with acute-on-chronic alcoholic hepatitis (AH). SPARC expression is increased on acute-on-chronic AH patients. Knockdown of SPARC decreased hepatic damage in the two models of liver injury. SPARC−/− mice showed a marked reduction in Con A-induced necroinflammation. Infiltration by CD4+ T cells, expression of tumor necrosis factor-α and interleukin-6 and apoptosis were attenuated in SPARC−/− mice. Sinusoidal endothelial cell monolayer was preserved and was less activated in Con A-treated SPARC−/− mice. SPARC knockdown reduced Con A-induced autophagy of cultured human microvascular endothelial cells (HMEC-1). Hepatic transcriptome analysis revealed several gene networks that may have a role in the attenuated liver damaged found in Con A-treated SPARC−/− mice. SPARC has a significant role in the development of Con A-induced severe liver injury. These results suggest that SPARC could represent a therapeutic target in acute liver injury.