Artículos (Genética)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10879

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The many ways to inhibit translation by Sorafenib in liver cancer cells
(Springer, 2025-09-15) Contreras Bernal, Laura; Ricciardi, Sara; Biffo, Stefano; Muntane Relat, Jordi; Cruz Díaz, Jesús de la; Genética; Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE); Instituto de Salud Carlos III
Sorafenib targets various tyrosine kinase receptors, inhibiting cell growth and proliferation, angiogenesis and metastasis in tumour cells. It is used to treat certain types of cancers including renal, thyroid and liver (hepatocellular carcinoma) cancers. Although Sorafenib is approved for advanced hepatocellular carcinoma, it only extends patient´s lives by a few months, highlighting the urgent need to better understand how it works and to develop more effective treatments. Sorafenib specifically inhibits translation initiation in hepatocellular carcinoma cells. Herein, we revealed that this inhibition results, at least, from the activation of PERK, triggering a stress response that leads to eIF2α phosphorylation, the inhibition of MNK1a-signalling-dependent eIF4E phosphorylation, and the aberrant assembly of the canonical eIF4F complex. Sorafenib also inhibits the ERK1/2 MAPK signalling in HepG2 cells. However, the mTORC1 pathway does appear to play a pivotal role in Sorafenib-dependent translation inhibition, as revealed by the phosphorylation levels of RPS6 and 4EBP1 proteins and the effects on translation of gene silencing 4EBP1/2 in Sorafenib-treated cells. Translation inhibition correlates with reduced production of cancer-promoting proteins like Cyclin D1 and c-Myc. Overexpression of the phosphomimetic eIF4E-S209D variant, which constitutively activates eIF4E, shows that inhibition of eIF4E phosphorylation directly causes Cyclin D1 down-regulation and cell-cycle delay in Sorafenib-treated cells. Taken together, our results confirm that Sorafenib induces translation reprogramming, whose understanding is crucial for improving its efficacy as a cancer therapy.
An essential gene screening identifies yeast Mot1 as a suppressor of R-loops and genome instability
(Public Library of Science, 2026-02-09) Soler Oliva, María Eugenia; Domínguez Sierra, Rocío de los Ángeles; Gaillard, Hélène; Aguilera López, Andrés; Genética; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Research Council (ERC); Fundación de Investigación de la Universidad de Sevilla
Transcription is essential for cellular function, but it can also lead to genetic instability, particularly through the formation of secondary structures such as R-loops, which consist of an RNA-DNA hybrid and a displaced DNA strand. Unscheduled R-loop accumulation is a major source of DNA damage and has been associated with several human diseases, including cancer. While multiple factors involved in RNA biogenesis, export, and chromatin remodeling play a role in preventing R-loop accumulation, the function of essential proteins in R-loop metabolism remains unexplored. Here, we performed a genetic screening in Saccharomyces cerevisiae using over 1200 temperature-sensitive mutants to identify novel proteins involved in the prevention of R-loop-associated genomic instability. Our results reveal that the SWI/SNF-like protein Mot1 plays a key role in preventing R-loop accumulation and R-loop-associated genome instability. Its role is particularly important during S phase, where Mot1 dysfunction leads to R-loop dependent replication impairment, presumably due to transcription-replication conflicts (TRCs). Epistatic relationships between mutations in MOT1 and the S-phase specific DNA-RNA helicase SEN1 further support the role of Mot1 in TRCs. The study highlights the importance of transcriptional regulators in maintaining genome stability by mitigating TRCs and regulating R-loop homeostasis.
The DExD-box RNA helicase Dbp7 unwinds short double-stranded RNAs
(Elsevier, 2026-02-12) Contreras Fernández, Julia Mª; Capeyrou, Régine; Henry, Yves; Henras, Anthony K.; Humbert, Odile; Cruz Díaz, Jesús de la; Villalobo Polo, Eduardo; Genética; Microbiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agence Nationale de la Recherche. France
DExD-box proteins are ATP-dependent enzymes that unwind double-stranded RNAs in a non-processive manner, often initiating strand separation from 5′- or 3′-single-stranded overhangs. Dbp7, a member of this family, is required for yeast ribosome biogenesis and has been specifically implicated in the release of the small nucleolar RNA snR190 from early pre-60S particles. To gain mechanistic insight into its function, we have examined the in vitro helicase activity of recombinant Dbp7. We show that it efficiently unwinds short double-stranded RNA substrates in an ATP-dependent manner, irrespective of overhang polarity, thereby establishing it as a bona fide DExD-box RNA helicase.
Regulation of NTRK2 alternative splicing by PRPF40B controls neural differentiation and synaptic plasticity
(Springer Nature, 2025-12-08) Duarte-Ruiz, María; Moreno-Castillo, Adela; El Yousfi, Younes; Moreno-Castro, Cristina; Martínez-Martínez, Noelia; Jiménez-Lozano, Sandra; Kennel, Marion; Ruiz-Rodríguez, Candela; Rodríguez-Caparrós, Alonso; López-Ros, Jennifer; de la Grange, Pierre; Hernández-Munain, Cristina; Suñé, Carlos; Genética; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Junta de Andalucía
BDNF signaling through its receptor TRKB plays a critical role in brain development, neuroplasticity, and homeostasis. Alternative splicing of the TRKB gene, NTRK2, generates either the full-length receptor (TRKB-FL) or a truncated isoform (TRKB-T1) that inhibits BDNF signaling and has been implicated in neurodegenerative diseases, psychiatric disorders, and cognitive impairments. Here, we show that PRPF40B, a splicing factor associated with neuronal dysfunction, promotes the production of the TRKB-FL isoform during neuronal differentiation. Silencing PRPF40B increases TRKB-T1 expression and impairs the expression of genes important for neuronal differentiation and synaptic plasticity, both in vitro and in vivo, during early embryogenesis. Our data thus identify PRPF40B as a key regulator of the balance between TRKB receptor isoforms, crucial for fine-tuning neuronal responses and for preventing neuroplasticity or survival impairments, providing also a mechanism for the role of PRPF40B in the pathogenesis of various human neurodegenerative diseases and psychiatric disorders. (Figure presented.)
Trigger factor accelerates nascent chain compaction and folding
(National Academy of Sciences, 2025-07-25) Till, Katharina; Seinen, Anne Bart; Wruck, Florian; Sunderlikova, Vanda; Galmozzi, Carla V.; Katranidis, Alexandros; Bukau, Bernd; Tans, Sander J.; Genética; European Union (UE)
Conformational control of nascent chains is poorly understood. Chaperones are knownto stabilize, unfold, and disaggregate polypeptides away from the ribosome. In compar-ison, much less is known about the elementary conformational control mechanisms atthe ribosome. Yet, proteins encounter major folding and aggregation challenges duringtranslation. Here, using selective ribosome profiling and optical tweezers with correlatedsingle- molecule fluorescence, with dihydrofolate reductase (DHFR) as a model system,we show that the Escherichia coli chaperone trigger factor (TF) accelerates nascentchain folding. TF scans nascent chains by transient binding events, and then locks intoa stable binding mode as the chain collapses and folds. This interplay is reciprocal: TFbinding collapses nascent chains and stabilizes partial folds, while nascent chain com-paction prolongs TF binding. Ongoing translation controls these cooperative effects,with TF- accelerated folding depending on the emergence of a peptide segment that iscentral to the core DHFR beta-sheet. The folding acceleration we report here impactsprocesses that depend on folding occurring cotranslationally, including cotranslationalprotein assembly, protein aggregation, and translational pausing, and may be relevantto other domains of life
Patulin and Xestoquinol are inhibitors of DNA topoisomerase 1
(National Academy of Sciences, 2025-04-24) Tumini, Emanuela; Wellinger, Ralf Erik; Herrera Moyano, Emilia; Navarro Cansino, Patricia; García Rubio, María Luisa; Salas Lloret, Daniel; Losada, Alejandro; Gaillard, Hélène; Luna Varo, Rosa María; Aguilera López, Andrés; Genética; Ministerio de Economía y Competitividad (MINECO). España; European Research Council (ERC); Agencia Estatal de Investigación. España
DNA topoisomerase 1 (TOP1) is essential for transcription, replication, and repair. Its function relies on two catalytic steps, DNA breakage and rejoining. Inhibitors of the second step prevent DNA rejoining and lead to persistent DNA breaks, acting as topoisomerase poisons, used as anticancer drugs. However, reliable inhibitors of the first step are not available. Here, we provide genetic and molecular evidence supporting that Patulin and, to a lesser extent, Xestoquinol inhibit the first catalytic step of TOP1 in vitro, in yeast and in human cells. Particularly, Patulin prevents the accumulation of TOP1 cleavage complexes caused by the TOP1 poison camptothecin (CPT) in human cells. Moreover, Patulin pretreatment of human or yeast cells reduces DNA damage and the accumulation of DNA breaks upon CPT exposure. Consistent with the protective role of TOP1 against harmful R-loops, Patulin treatment increases R-loops and R-loop-associated cytotoxicity, mimicking the effect of TOP1 silencing. Altogether our findings indicate that Patulin and Xestoquinol are nonpoisoning inhibitors of TOP1, which should potentiate new research approaches in molecular biology and medicine.
Biodegradable polyacrylamide-based hydrogels with unique bactericidal and osteoinductive properties to improve the clinical success of porous titanium implants
(Elsevier, 2026-01) Martínez Muñoz, Guillermo; Castellano Pozo, Maikel; Merinero de los Santos, Manuel; Casado Jurado, David; Huertas Sánchez, Pablo; Pajuelo Domínguez, Eloísa; Miguel Rodríguez, Manuel de; Begines Ruiz, Belén; Torres Hernández, Yadir; Alcudia Cruz, Ana; Química Orgánica; Genética; Microbiología y Parasitología; Citología e Histología Normal y Patológica; Ingeniería y Ciencia de los Materiales y del Transporte; Química Orgánica y Farmacéutica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Stress-shielding phenomenon, infections, and limited bone integration are traditional drawbacks associated with titanium implants. Biodegradable polyacrylamide-based hydrogels synthesized with an 8-fold scaled up, disulfide bond-containing crosslinker, were prepared to overcome these limitations. Hydrogels' biodegradability in the presence of glutathione has been demonstrated. Additionally, hydrogels exhibited strong antibacterial activity against pathogens such as P. aeruginosa and S. aureus, along with promising osseointegrative properties, in vitro fibroblast (CCL-1) viability, and in vivo biocompatibility in C. elegans. Porous titanium (Ti) fabricated via space-holder technique were infiltrated with previously described hydrogels. The optimal system, featuring a 4 wt% crosslinked acrylamide-based hydrogel infiltrated into 60 vol%, 355–500 μm Ti substrate, showed excellent biomechanical integrity and biofunctionality, supporting its potential as a safe and effective bone implant. Additionally, the study introduces streamlined, cost-effective methodologies for implant testing and characterization.
Structured Promoter Variability in Epigenetically Regulated Operons Contributes to Surface Adaptation in Salmonella
(Wiley, 2026-02-12) Fernández Fernández, Rocío; Gutiérrez Pozo, Gabriel; Piubeli, Francine; Garmendia, Junkal; Beuzón, Carmen R.; Sánchez Romero, María Antonia; Microbiología y Parasitología; Genética; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Bacterial adaptation to dynamic and hostile environments often relies on the ability to modify surface structures, which are subjected to strong selective pressures. While mutations in coding sequences that alter surface structures have long been recognised as key drivers of bacterial adaptation, this study reveals structured promoter variation as a novel additional layer of functional adaptation. Focusing on the opvAB operon in Salmonella, epigenetically regulated by the coordinated action of Dam methylation and OxyR binding, we investigated the evolutionary dynamics and regulatory architecture of its regulatory region. Comparative genomics of Salmonella subspecies revealed striking variability in this regulatory region. Notably, the opvAB promoter exhibited mutations clustering at specific, recurrent positions, suggesting lineage-specific fine-tuning through structured and potentially functional variability, further demonstrated experimentally by phase variation analysis within clonal populations at the single bacterial cell level. Our findings highlight a potentially overlooked evolutionary mechanism by which bacteria can modulate gene expression through a balance between conservation and variability in regulatory elements. This structured promoter variation likely complements genetic and epigenetic strategies, offering a new perspective on how bacterial populations adapt to environmental challenges.
Unveiling balanced prenatal microbial colonization in amniotic fluid through an integrated culture and sequencing approach
(Springer Nature, 2026-01-09) González Rovira, María; Sáinz Bueno, José Antonio; García Díaz, Lutgardo; Martínez-Pancorbo, C.; Sánchez, J.; Gutiérrez Pozo, Gabriel; Magoutas, K.; Mesías-Pérez, A.; Mellado Durán, María Encarnación; Payne, M.; Sousa Martín, Carolina; Moreno Amador, María de Lourdes; Microbiología y Parasitología; Cirugía; Genética; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Federación de Asociaciones de Celíacos de España (FACE); Universidad de Sevilla
Background The evidence of a low-biomass microbial community in the amniotic fluid (AF) is challenging the traditional concept of a sterile womb. To clarify microbial presence and host responses, a comprehensive, multi-methodological approach is required. Methods We designed an optimized culturing strategy that maximized microorganism recovery by implementing differential centrifugation and concentration of AF samples, followed by plating onto four distinct selective media types and incubation under both stringent aerobic (up to two weeks) and prolonged anaerobic (up to four weeks) conditions, including an initial pre-enrichment step in Brain Heart Infusion (BHI) broth for low-abundance organisms. These results were combined with PacBio 16S rRNA gene sequencing, Illumina shotgun metagenomics, and antimicrobial peptides (AMP) detection. Using this approach, we characterized microbial presence in 154 AF samples across gestational stages. Data normality was assessed with the Shapiro-Wilk test, guiding the selection of both parametric and non-parametric tests, and a p-value of < 0.05 was considered statistically significant. Results We detected culturable microorganisms in 33.1% of samples, with a higher proportion in elective caesarean Sect. (55.0%) compared to amniocentesis (29.5%), suggesting increased microbial load toward term. We applied stringent contamination controls, and repeatedly recovered viable microorganisms Bacillus, Cutibacterium, Micrococcus, and Staphylococcus, with Cutibacterium acnes and Staphylococcus epidermidis common. Both sequencing methods revealed a low-biomass, low-diversity microbial community with high inter-individual variability. Notably, striking microbial discordance in diamniotic twin pregnancies, challenged intrauterine homogeneity. Higher Human Beta Defensin (HBD) -1 levels correlated with absence of culturable bacteria or microbial DNA, while levels of HBD-1, HBD-3, and LL-37 were reduced in Staphylococcus-positive samples, suggesting a dynamic interplay between specific bacteria and host defences. Conclusions Our findings indicate that viable bacteria and/or DNA can transiently access the prenatal environment microbial balance. We propose a novel perspective of a potential regulatory axis between microorganisms and AMP.
Cis- and Trans-Regulatory Mechanisms of Gene Expression in the ASJ Sensory Neuron of Caenorhabditis elegans
(Oxford University Press, 2015-05-01) González-Barrios, María; Fierro-González, Juan Carlos; Krpelanova, Eva; Mora Lorca, José Antonio; Rafael Pedrajas, José; Peñate Salas, Xenia; Chávez de Diego, Sebastián; Swoboda, Peter; Jansen, Gert; Miranda-Vizuete, Antonio; Genética; Farmacología; Japanese Ministry of Education, Culture, Sport, Science and Technology; Junta de Andalucía
The identity of a given cell type is determined by the expression of a set of genes sharing common cis-regulatory motifs and being regulated by shared transcription factors. Here, we identify cis and trans regulatory elements that drive gene expression in the bilateral sensory neuron ASJ, located in the head of the nematode Caenorhabditis elegans. For this purpose, we have dissected the promoters of the only two genes so far reported to be exclusively expressed in ASJ, trx-1 and ssu-1. We hereby identify the ASJ motif, a functional cis-regulatory bipartite promoter region composed of two individual 6 bp elements separated by a 3 bp linker. The first element is a 6 bp CG-rich sequence that presumably binds the Sp family member zinc-finger transcription factor SPTF-1. Interestingly, within the C. elegans nervous system SPTF-1 is also found to be expressed only in ASJ neurons where it regulates expression of other genes in these neurons and ASJ cell fate. The second element of the bipartite motif is a 6 bp AT-rich sequence that is predicted to potentially bind a transcription factor of the homeobox family. Together, our findings identify a specific promoter signature and SPTF-1 as a transcription factor that functions as a terminal selector gene to regulate gene expression in C. elegans ASJ sensory neurons.
Mother cells can establish slow-growing lineages in clonal populations since their earliest division cycles
(The Royal Society, 2026-01-01) Delgado Román, Irene; García Marcelo, María José; Ruger Herreros, Carmen; Delgado Ramos, Lidia; Singh, Abhyudai; Chávez de Diego, Sebastián; Muñoz Centeno, María de la Cruz; Genética; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Union (UE); Junta de Andalucía
Clonal populations exhibit phenotypic variation despite being composed of genetically identical cells under the same environmental conditions. The proliferation rate also shows this heterogeneity, but the underlying mechanisms remain poorly understood. In this study, we combined single-cell microencapsulation with confocal microscopy to develop a new experimental approach for analysing budding yeast cell lineages and determining the age of every cell within each microcolony. We found that most slow-growing lineages are founded by young mother cells that have undergone only a few cell divisions, typically between one and four. This reduction in proliferative capacity is linked to the expression levels of the cell cycle regulator Whi5, which increase with the number of replication cycles, even since the earliest stages. We also found that the increased levels of Whi5 are due to the higher accumulation of its mRNA during the S/G2/M phases of young mother cells compared to newborn cells. Our results show that the proliferative structure of a cell population is progressively shaped in each mitotic cycle, starting from the very first division, when a mother cell has the opportunity to establish a slowly proliferating lineage. Possible mechanisms of Whi5 action to mediate this effect are discussed.
ColorPhAST: a visual rapid colorimetric assay for detecting phage-susceptibility in Escherichia coli
(Frontiers Media S.A., 2025-07-11) Gómez Estévez, Paula; Rodríguez Villodres, Ángel; Gálvez Benítez, Lydia; Martín Gutiérrez, Guillermo; Cisneros, José Miguel; Rosa Utrera, José Manuel de la; Lepe Jiménez, José Antonio; Genética; Medicina; Electrónica y Electromagnetismo; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
The alarming increase in the prevalence of multidrug-resistant microorganisms, which in some cases has left no available treatment options, has led to a renewed interest in previously abandoned therapeutic approaches such as bacteriophage therapy. Therefore, the development of rapid methods for determining phage susceptibility will be essential in the near future because phage-based treatments could provide a viable alternative for patients with infections caused by multidrugresistant microorganisms. In response to this need, a new test named ColorPhAST (Color Phage Activity Susceptibility Test) based on color change of red phenol has been designed to detect phage-susceptibility in just 2 h. A total of 100 Escherichia coli isolates were used to evaluate the performance of the test, 55 being resistant to the isolated phage through the double agar overlay spot assay (gold standard method). The sensitivity and specificity of the test were 95.6 and 100%, respectively. The ColorPhAST is a fast, easy-to-performed, and accurate method with great potential for identifying susceptibility to bacteriophages.
H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death
(Springer Nature, 2025-11) Rubio Contreras, Diana; Hidalgo-García, Daniel; Angulo-Jiménez, Carmen; Granado Calle, Esperanza; Sabio-Bonilla, Margarita; Ruiz Pérez, José Francisco; Gómez Herreros, Fernando; Bioquímica Vegetal y Biología Molecular; Genética; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España
DNA single-strand break (SSB) repair defects lead to hereditary neurological syndromes. Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1), is caused by the homozygous H493R mutation in tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that initiates the repair of DNA topoisomerase 1 (TOP1)-induced SSBs by unlinking the TOP1 peptide from the break. Although TDP1 also initiates the repair of TOP1-induced DNA double-strand breaks (DSBs) associated with transcription, the role of TOP1-induced DSBs in SCAN1 pathology remains unclear. Here, we have addressed the impact of the SCAN1/H493R mutation on the repair of TOP1-induced DSBs. We demonstrate that while TDP1 loss delays the repair of these breaks, SCAN1/H493R completely blocks it in RPE-1 quiescent cells. This blockage is specific to DSBs and is accompanied by a prolonged trapping of mutated TDP1 on DNA, but not of TOP1 cleavage complexes (TOP1cc). Intriguingly, the H263A inactivating mutation of TDP1, which accumulates TOP1cc, also blocks TOP1-induced DSB repair. Importantly, both SCAN1/H493R and H263A mutations exhibit genome instability and cell death. Moreover, we demonstrate that tyrosyl-DNA phosphodiesterase 2 (TDP2) can compensate for TDP1 loss in RPE-1 quiescent cells. Collectively, our data support the potential role of TOP1-induced DSBs as a main contributor to certain hereditary neurological syndromes.
TOP2B modulates DNA supercoiling and chromatin contacts during transcriptional induction
(American Association for the Advancement of Science, 2025-11-26) Terrón Bautista, José; Bejarano Franco, Marina; Martínez Sánchez, María del Mar; López Hernández, Laura; Díaz Maldonado, Héctor; Santiago Gómez, Angélica; Kidane, Sara; Aguilera López, Andrés; Millán Zambrano, Gonzalo; Cortés Ledesma, Felipe; Genética; European Union (UE); Ministerio de Ciencia e Innovación (MICIN). España; European Research Council (ERC); Junta de Andalucía; National Institutes of Health. United States; Agencia Estatal de Investigación. España
Human type-II topoisomerases, TOP2A and TOP2B, resolve transcription-associated DNA supercoiling, therebyinfluencing gene expression programs, and have been recently linked to three-dimensional genome architecturethrough yet poorly understood mechanisms. Here, we investigate the regulatory roles of TOP2 paralogs usingestrogen signaling, which triggers an acute transcriptional induction that involves extensive rewiring of genomeorganization, as a model system. Unexpectedly, we find that estrogen treatment strongly inhibits TOP2B catalyticactivity—although not its binding—specifically at estrogen-responsive enhancers and promoters. This inhibitionresults in an accumulation of negative DNA supercoiling and promotes the formation of regulatory chromatincontacts. Estrogen-mediated inhibition of TOP2B activity depends on estrogen receptor α, a noncatalytic functionof TOP2A, and, most importantly, the action of zinc finger protein associated with tyrosyl-DNA phosphodiesterase2 and TOP2, an atypical small ubiquitin-like modifier ligase that directly inhibits TOP2 activity. This mechanism oftranscriptional control, involving the fine-tuning of DNA supercoiling levels, highlights the role of DNA topoisom-erases as central regulators of genome dynamics.
Body-wide synchronization of insulin-signaling dependent DAF-16/FOXO nuclear translocation pulses correlated with C. elegans growth
(Springer Nature, 2025-12-11) Demirbas, Burak; Filina, Olga; Louisse, Timo; Natarajan, Ananya; Goos, Yvonne; Sánchez Romero, María Antonia; Olmedo López, María; van Zon, Jeroen S.; Microbiología y Parasitología; Genética; Dutch Research Council (NWO); Ministerio de Ciencia, Innovación y Universidades (MICIU). España; National Institutes of Health-Office of Research Infrastructure Programs
Insulin signaling is the core pathway regulating body growth, but the dynamics of insulin signaling across an organism has not been studied experimentally. By imaging C. elegans larvae in microchambers, we follow the key insulin signaling step, DAF-16/FOXO nuclear translocation, at cellular level throughout the body. We show that under constant stress, translocation occurs in stochastic pulses, but with each translocation pulse occurring near-simultaneously in all cells. Pulsatile DAF-16/FOXO translocation is correlated with growth, as periods of long or frequent pulses coincide with bouts of growth arrest, and short, infrequent pulses with body growth, while the animal’s ability to arrest growth is lost in daf-16/FOXO mutants. Organism-wide coordination of DAF-16/FOXO translocation pulses might thus be important to ensure uniformity of body growth, with potential implications for understanding tissue- and body-wide coordination of insulin-dependent processes also in humans.
The interplay between Caenorhabditis elegans larval development and Orsay virus infection
(Cell Press, 2025-12) Melero, Izan; Castiglioni, Victoria G.; Olmo-Uceda, María J.; Villena-Jiménez, Ana; Olmedo López, María; González, Rubén; Santiago F., Elena; Genética; BIO371: Genética del Desarrollo en Organismos Modelo
The development of Caenorhabditis elegans is tightly regulated and highly sensitive to environmental cues, including pathogens. While the effects of bacterial and fungal infections on development have been studied, the influence of viral infections remains poorly understood. We investigate the bidirectional relationship between C. elegans larval development and infection by its natural enteric pathogen Orsay virus (OrV). We show that OrV can replicate efficiently during molting periods and that infection initiated in more developed larvae leads to significantly higher viral loads and broader intestinal cell infection. Conversely, OrV infection perturbs the expression of developmental regulators and alters the timing of larval transitions: it accelerates the first molt and delays the subsequent stages, ultimately resynchronizing overall developmental timing. These findings suggest that developmental transitions create windows of altered antiviral capacity. Our work highlights trade-offs between developmental progression and immune competence, offering new insights into how host-pathogen interactions are shaped by development.
Harnessing coumarin-thio(seleno)cyanate conjugates: potent In vivo antiproliferative agents targeting carbonic anhydrases
(Taylor & Francis, 2025-10-10) Meza Ireta, Silvia Alejandra; Romero Hernández, Laura L.; Begines Aguilar, Paloma; Giouvannuzi, Simone; Puerta, Adrián; Romero Franco, Amador; Huertas Sánchez, Pablo; Fernández-Bolaños Guzmán, José María; Castellano Pozo, Maikel; López López, Óscar; Química Orgánica y Farmacéutica; Genética; Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; European Union (UE)
We synthesised coumarin-based derivatives bearing thio- and selenocyanates to selectively inhibit tumour-associated carbonic anhydrases (CAs) IX and XII and to exert antiproliferative effects on tumour cells. Structural variations included chalcogen atom type (S, Se), substitutions at C-3/C-4, and tether length at C-7 of the coumarin core. Thiocyanates 4 and 7b showed potent CA IX/XII inhibition (Ki = 17.9–27.4nM) with >5000-fold selectivity over off-target isoforms (CAs I and II). Selenocyanate 8a exhibited strong antiproliferative activity (GI 50 = 0.78–2.6µM) across six human solid tumour cell lines. Mechanistic studies revealed a cytostatic effect via cell cycle arrest and reduced mitotic progression. In vivo assays in Caenorhabditis elegans confirmed selective cytostatic action of selenocyanate 8c, reducing tumorous germline size without affecting healthy tissues at therapeutic doses.
Epigenetic control of the ferric uptake regulator (Fur) and fumarate nitrate reductase (FNR) master regulatory proteins contributes to Haemophilus influenzae survival during lung infection
(American Society for Microbiology, 2025-08) Gil-Campillo, Celia; Euba, Begoña; Rodríguez-Arce, Irene; San León, David; Marino, Mary C.; Asensio-López, Javier; Gutiérrez Pozo, Gabriel; Sánchez Romero, María Antonia; Garmendia, Junkal; Genética; Microbiología y Parasitología; Agencia Estatal de Investigación. España; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Sociedad Española de Neumología y Cirugía Torácica (SEPAR); Gobierno de Navarra
DNA regulatory elements that dictate how the bacterial pathobiont Haemophilus influenzae infects and adapts to the airways of immunocompromised patients suffering from chronic obstructive pulmonary disease (COPD) are poorly understood. This is in part due to the scarcity of research integrating genetic and epigenetic perspectives to shed light on the role of distinct bacterial adaptive strategies within the human airways. In this work, global fitness profilingof H. influenzae mutants by high-throughput transposon mutant sequencing within the mouse lung identified Dam methyltransferase as an in vivo requirement for respiratory infection. Equally, single-molecule real-time sequencing methylome analyses found undermethylation of GATC motifs within putative regulatory elements and revealed the first case of phenotypic variation controlled by variable Dam methylation in H. influenzae. Moreover, RNA sequencing differentialgene expression disclosed a novel regulatory network where Dam methyltransferase positively regulates the expression of the ferric uptake regulator (Fur), which in turn represses the expression of the fumarate nitrate reductase (FNR) regulator and, subsequently, of a repertoire of genes that belong to the FNR regulon and encode bacterial anaerobic defenses against, among others, reactive nitrogen species produced within the diseased airways. Our results present a multifactorial regulatory network where the interplay between the Fur and FNR master transcriptional regulators is controlled epigenetically by Dam methylation. We put forward the notion that this network regulates H. influenzae survival in diseased airway niches with high nitrosative stress where damage reduces the amount of oxygen in the lungs, as encountered in COPD.
DNA topoisomerase II promotes N6-adenosine mRNA methylation
(Elsevier, 2025-10-30) Megías Fernández, Clara; Delgado Sainz, Irene; León Halcón, Alberto; Buglioni, Valentina; Bruno, Federica; González Aguilera, Cristina; Maslon, Magdalena M.; Jimeno González, Silvia; Genética; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; Junta de Andalucía; European Union (UE)
DNA topoisomerase II (TOP2) is an enzyme that regulates DNA topology, primarily by removing DNA supercoiling. This function is crucial during transcription, as the movement of RNA polymerase II (RNAPII) generates torsional stress. However, the specific role of TOP2 in the regulation of gene expression remains to be fully elucidated, as both TOP2 inhibitors and poisons have been shown to upregulate specific genes. In this study, we show that TOP2 poisoning negatively affects transcription elongation of genes repressed at the level of promoter-proximal pausing. Importantly, this effect is counteracted by defective mRNA N6 -denosine methylation (m6A), which results in altered RNA turnover and pre-mRNA splicing. We propose that TOP2 serves a dual function, supporting the maintenance of basal transcription elongation while simultaneously promoting m6A modification in pre-mRNAs to reduce the overall gene expression output.
O-mannosylation of misfolded ER proteins promotes ERAD
(Springer Nature, 2025-12-05) Lemus Rodríguez,Leticia; Meyer, Hadar; Rodriguez-Rosado, Ana, I.; Schuldiner, Maya; Goder, Veit; Genética; European Union (UE); Agencia Estatal de Investigación. España
Protein quality control (PQC) in the secretory pathway, a process critically linked to numerous human diseases, begins in the endoplasmic reticulum (ER) and involves ER-associated degradation (ERAD) of terminally misfolded proteins. In this study, we conducted genome-wide screens in baker’s yeast (Saccharomyces cerevisiae) to investigate the degradation of Gas1*, a misfolded version of an O-mannosylated, glycosylphosphatidylinositol (GPI)-anchored protein. In combination with detailed biochemical and genetic analyses, these screens revealed an unexpected bifunctionality of the evolutionarily conserved heteromeric enzyme complex Pbn1-Gpi14: while it has been previously recognized as a GPI-mannosyltransferase, we here find that it catalyzes the O-mannosylation of misfolded proteins, thereby promoting their ERAD. This process is particularly relevant for misfolded proteins that lack N-glycans. Our results suggest that protein O-mannosylation constitutes a distinct type of glycan-dependent mechanism for promoting ERAD.

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