Enantioselective regulation of lactate racemization by LarR in Lactobacillus plantarum.

Lactobacillus plantarum is a lactic acid bacterium that produces a racemic mixture of l- and d-lactate from sugar fermentation. The interconversion of lactate isomers is performed by a lactate racemase (Lar) that is transcriptionally controlled by the l-/d-lactate ratio and maximally induced in the presence of l-lactate. We previously reported that the Lar activity depends on the expression of two divergently oriented operons: (i) the larABCDE operon encodes the nickel-dependent lactate racemase (LarA), its maturases (LarBCE), and a lactic acid channel (LarD), and (ii) the larR(MN)QO operon encodes a transcriptional regulator (LarR) and a four-component ABC-type nickel transporter [Lar(MN), in which the M and N components are fused, LarQ, and LarO]. LarR is a novel regulator of the Crp-Fnr family (PrfA group). Here, the role of LarR was further characterized in vivo and in vitro. We show that LarR is a positive regulator that is absolutely required for the expression of Lar activity. Using gel retardation experiments, we demonstrate that LarR binds to a 16-bp palindromic sequence (Lar box motif) that is present in the larR-larA intergenic region. Mutations in the Lar box strongly affect LarR binding and completely abolish transcription from the larA promoter (PlarA). Two half-Lar boxes located between the Lar box and the -35 box of PlarA promote LarR multimerization on DNA, and point mutations within one or both half-Lar boxes inhibit PlarA induction by l-lactate. Gel retardation and footprinting experiments indicate that l-lactate has a positive effect on the binding and multimerization of LarR, while d-lactate antagonizes the positive effect of l-lactate. A possible mechanism of LarR regulation by lactate enantiomers is proposed

New molecular insights into human telomere transcription and the ALTernative telomere maintenance mechanism

Telomeres are specialized structures protecting chromosome ends. They are made of telomeric DNA, the shelterin protein complex and TERRA telomeric-repeat containing RNA, a product of telomere transcription. Divisions of normal somatic cells progressively shorten telomeres while this is counteracted by the activation of telomerase in about 85% of human tumors or an alternative homologous-recombination based mechanism, dubbed ALT, in 5 10% of tumours. Since ALT is not active in normal cells, it represents an interesting target for cancer therapy. We first studied TERRA regulation and found that, both in vitro and in vivo, in human muscles, AMPK stimulates NRF1/PGC1α-dependent transcription of telomeres, thus linking telomeres to metabolism. Then, we identified TSPYL5 as a possible molecular target for ALT therapy as the protein is specifically required to protect POT1 shelterin protein from proteasome degradation in ALT+ cells through regulation of TPP1, its binding partner at telomeres.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

TSPYL5 depletion induces specific death of ALT cells through USP7-dependent proteasomal degradation of POT1

A significant fraction (~10%) of cancer cells maintain their telomere length via a telomerase-independent mechanism known as Alternative Lengthening of Telomeres(ALT). Currently, there are no known molecular, ALT-specific, therapeutic target. We have identified TSPYL5 (Testis Specific Y-encoded-Like Protein 5) as a PML body component, co-localizing with ALT telomeres and critical for ALT+ cell viability. TSPYL5 was described as an inhibitor of the USP7 deubiquitinase. We report that TSPYL5 prevents the poly-ubiquitination of POT1 – a shelterin component – and protects POT1 from proteasomal degradation, exclusively in ALT+ cells. USP7 depletion rescued POT1 poly-ubiquitination and loss, suggesting that the deubiquitinase activates POT1 E3 ubiquitin ligase(s). Similarly, PML depletion suppressed POT1 poly-ubiquitination, suggesting an interplay between USP7 and PML to trigger POT1 degradation in TSPYL5-depleted ALT+ cells. We demonstrate that ALT telomeres need to be protected from POT1 degradation in ALT-associated PML bodies, and identify TSPYL5 as a ALT+ cancer-specific therapeutic target

Le scolyte des fruits du caféier,

Hypothenemus hampei (Ferrari) ou scolyte des fruits du caféier est le ravageur le plus redoutable pour cette culture. Il est actuellement présent dans la presque totalité des régions productrices de café dans le monde, le dernier grand territoire atteint étant la Papouasie Nouvelle Guinée, où il a été officiellement signalé en 2017. Le scolyte a également été découvert dans deux départements français d’Outre-mer d’où il était absent jusqu’alors, la Martinique en 2012, puis tout récemment la Guadeloupe en début d’année 2021. Il représente pour cette région une menace pour l’existence même de la caféiculture qui fait partie de son patrimoine historique. Le scolyte a été détecté à la périphérie puis au cœur de la zone où le caféier est traditionnellement cultivé. Les mesures prises par les autorités locales pour freiner la dispersion du ravageur donnent déjà suite à des recommandations en matière de lutte qui seront adaptées à la situation agronomique et économique de la filière café

Towards Theranostic Applications of Trifluoromethyl-Substituted Iridium(III) complexes

info:eu-repo/semantics/nonPublishe

Endurance training alleviates MCP-1 and TERRA accumulation at old age in human skeletal muscle.

Both oxidative stress and telomere transcription are up-regulated by acute endurance exercise in human skeletal muscle. Whether and how life-long exercise training influences the antioxidant system response at transcriptional level and TERRA expression is unknown, especially during aging. Response to acute endurance exercise was investigated in muscle biopsies of 3 male subjects after 45 min of cycling. MCP-1 and SOD1 mRNA levels increased up to, 15-fold and 63%, respectively, after the cycling session while the mRNA levels of SOD2 were downregulated by 25%. The effects of chronic endurance exercise and aging were tested in the blood and muscle of 34 male subjects divided into four groups: young (YU) or old (OU) untrained, young (YT) or old (OT) trained cyclists. Long-term endurance training limited the age-dependent elevation in SOD1 (OT vs OU, -26%, P = 0.03) and the decline in SOD2 mRNA levels (OU vs YU, -41%, P = 0.04). A high endurance training status alleviated the age-related increase in the aging biological marker MCP-1 in plasma (OU vs YU, +48%, P = 0.005). Similar results were observed for telomeric transcription as the age-associated increase in 16p TERRA levels (OU vs YU, +39%, P = 0.001) was counteracted by a high endurance training status (OT vs OU, -63%, P = 0.0005). In conclusion, as MCP-1, we propose that the age-related TERRA accumulation might represent a novel biological marker of aging. Those aging-related increase expression might be alleviated by a high endurance training status. Whether those biological markers of aging are linked to an elevation of oxidative stress is still an open question. Therefore, whether the positive adaptations provided by endurance training indeed reduce oxidative stress, including at telomeres, and whether TERRA plays any role in this, need to be further investigated

TSPYL5 depletion induces specific death of ALT cells through USP7-dependent proteasomal degradation of POT1

A significant fraction (~10%) of cancer cells maintain their telomere length via a telomerase-independent mechanism known as Alternative Lengthening of Telomeres (ALT). Currently, there are no known molecular, ALT-specific, therapeutic target. We have identified TSPYL5 (Testis Specific Y-encoded-Like Protein 5) as a PML body component, co-localizing with ALT telomeres and critical for ALT+ cell viability. TSPYL5 was described as an inhibitor of the USP7 deubiquitinase. We report that TSPYL5 prevents the poly-ubiquitination of POT1 – a shelterin component – and protects POT1 from proteasomal degradation, exclusively in ALT+ cells. USP7 depletion rescued POT1 poly-ubiquitination and loss, suggesting that the deubiquitinase activates POT1 E3 ubiquitin ligase(s). Similarly, PML depletion suppressed POT1 poly-ubiquitination, suggesting an interplay between USP7 and PML to trigger POT1 degradation in TSPYL5-depleted ALT+ cells. We demonstrate that ALT telomeres need to be protected from POT1 degradation in ALT-associated PML bodies, and identify TSPYL5 as a ALT+ cancer-specific therapeutic target

Exploring the phototoxicity of hypoxic active iridium(III)-based sensitizers in 3D tumor spheroids

Among all molecules developed for anticancer therapies, photodynamic therapeutic agents have a unique profile. Their maximal activity is specifically triggered in tumors by light, and toxicity of even systemically delivered drug is prevented in nonilluminated parts of the body. Photosensitizers exert their therapeutic effect by producing reactive oxygen species via a light-activated reaction with molecular oxygen. Consequently, the lowering of pO2 deep in solid tumors limits their treatment and makes essential the design of oxygen-independent sensitizers. In this perspective, we have recently developed Ir(III)-based molecules able to oxidize biomolecules by type I processes under oxygen-free conditions. We examine here their phototoxicity in relevant biological models. We show that drugs, which are mitochondria-accumulated, induce upon light irradiation a dramatic decrease of the cell viability, even under low oxygen conditions. Finally, assays on 3D tumor spheroids highlight the importance of the light-activation step and the oxygen consumption rate on the drug activity