Investigación

URI permanente para esta comunidadhttps://hdl.handle.net/11441/10690

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A novel lncRNA as a positive regulator of carotenoid biosynthesis in Fusarium
(Nature Research, 2020) Parra Rivero, Obdulia; Pardo Medina, Javier; Gutiérrez Pozo, Gabriel; Limón Mirón, María del Carmen; Ávalos Cordero, Francisco Javier; Universidad de Sevilla. Departamento de Genética
The fungi Fusarium oxysporum and Fusarium fujikuroi produce carotenoids, lipophilic terpenoid pigments of biotechnological interest, with xanthophyll neurosporaxanthin as the main end product. Their carotenoid biosynthesis is activated by light and negatively regulated by the RING-finger protein CarS. Global transcriptomic analysis identified in both species a putative 1-kb lncRNA that we call carP, referred to as Fo-carP and Ff-carP in each species, upstream to the gene carS and transcribed from the same DNA strand. Fo-carP and Ff-carP are poorly transcribed, but their RNA levels increase in carS mutants. The deletion of Fo-carP or Ff-carP in the respective species results in albino phenotypes, with strong reductions in mRNA levels of structural genes for carotenoid biosynthesis and higher mRNA content of the carS gene, which could explain the low accumulation of carotenoids. Upon alignment, Fo-carP and Ff-carP show 75-80% identity, with short insertions or deletions resulting in a lack of coincident ORFs. Moreover, none of the ORFs found in their sequences have indications of possible coding functions. We conclude that Fo-carP and Ff-carP are regulatory lncRNAs necessary for the active expression of the carotenoid genes in Fusarium through an unknown molecular mechanism, probably related to the control of carS function or expression
A protease-mediated mechanism regulates the cytochrome c6/plastocyanin switch in Synechocystis sp. PCC 6803
(NAS, 2021-01-25) García Cañas, Raquel María; Giner Lamia, Joaquín; Florencio Bellido, Francisco Javier; López Maury, Luis; Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular; Ministerio de Economia, Industria y Competitividad (MINECO). España; Agencia Estatal de Investigación. España; Junta de Andalucía; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
After the Great Oxidation Event (GOE), iron availability was greatly decreased, and photosynthetic organisms evolved several alternative proteins and mechanisms. One of these proteins, plastocyanin, is a type I blue-copper protein that can replace cytochrome c6 as a soluble electron carrier between cytochrome b6f and photosystem I. In most cyanobacteria, expression of these two alternative proteins is regulated by copper availability, but the regulatory system remains unknown. Herein, we provide evidence that the regulatory system is composed of a BlaI/CopY-family transcription factor (PetR) and a BlaR-membrane protease (PetP). PetR represses petE (plastocyanin) expression and activates petJ (cytochrome c6), while PetP controls PetR levels in vivo. Using whole-cell extracts, we demonstrated that PetR degradation requires both PetP and copper. Transcriptomic analysis revealed that the PetRP system regulates only four genes (petE, petJ, slr0601, and slr0602), highlighting its specificity. Furthermore, the presence of petE and petRP in early branching cyanobacteria indicates that acquisition of these genes could represent an early adaptation to decreased iron bioavailability following the GOE.
Contribution of DNA adenine methylation to gene expression heterogeneity in Salmonella enterica
(Oxford University Press, 2020) Sánchez Romero, María Antonia; Rodríguez Olivenza, David; Gutiérrez Pozo, Gabriel; Casadesús Pursals, Josep; Universidad de Sevilla. Departamento de Genética; Ministerio de Ciencia e Innovación (MICIN). España
Expression of Salmonella enterica loci harboring undermethylated GATC sites at promoters or regulatory regions was monitored by single cell analysis. Cell-to-cell differences in expression were detected in ten such loci (carA, dgoR, holA, nanA, ssaN, STM1290, STM3276, STM5308, gtr and opvAB), with concomitant formation of ON and OFF subpopulations. The ON and OFF subpopulation sizes varied depending on the growth conditions, suggesting that the population structure can be modulated by environmental control. All the loci under study except STM5308 displayed altered patterns of expression in strains lacking or overproducing Dam methylase, thereby confirming control by Dam methylation. Bioinformatic analysis identified potential binding sites for transcription factors OxyR, CRP and Fur, and analysis of expression in mutant backgrounds confirmed transcriptional control by one or more of such factors. Surveys of gene expression in pairwise combinations of Dam methylation-dependent loci revealed independent switching, thus predicting the formation of a high number of cell variants. This study expands the list of S. enterica loci under transcriptional control by Dam methylation, and underscores the relevance of the DNA adenine methylome as a source of phenotypic heterogeneity.
Functional diversity of motoneurons in the oculomotor system
(National Academy of Sciences, 2019-02-26) García Hernández, Rosendo Miguel; Martín Calvo, Paula; Blumer, Roland; Rodríguez de la Cruz, Rosa María; Pastor Loro, Ángel Manuel; Universidad de Sevilla. Departamento de Fisiología
Extraocular muscles contain two types of muscle fibers according to their innervation pattern: singly innervated muscle fibers (SIFs), similar to most skeletal muscle fibers, and multiply innervated muscle fibers (MIFs). Morphological studies have revealed that SIF and MIF motoneurons are segregated anatomically and receive different proportions of certain afferents, suggesting that while SIF motoneurons would participate in the whole repertoire of eye movements, MIF motoneurons would contribute only to slow eye movements and fixations. We have tested that proposal by performing single-unit recordings, in alert behaving cats, of electrophysiologically identified MIF and SIF motoneurons in the abducens nucleus. Our results show that both types of motoneuron discharge in relation to eye position and velocity, displaying a tonic–phasic firing pattern for different types of eye movement (saccades, vestibulo-ocular reflex, vergence) and gaze-holding. However, MIF motoneurons presented an overall reduced firing rate compared with SIF motoneurons, and had significantly lower recruitment threshold and also lower eye position and velocity sensitivities. Accordingly, MIF motoneurons could control mainly gaze in the off-direction, when less force is needed, whereas SIF motoneurons would contribute to increase muscle tension progressively toward the on-direction as more force is required. Anatomically, MIF and SIF motoneurons distributed intermingled within the abducens nucleus, with MIF motoneurons being smaller and having a lesser somatic synaptic coverage. Our data demonstrate the functional participation of both MIF and SIF motoneurons in fixations and slow and phasic eye movements, although their discharge properties indicate a functional segregation.
Human mitochondrial degradosome prevents harmful mitochondrial R loops and mitochondrial genome instability
(2018) Silva, Sonia; Pérez de Camino Cantos, Dolores; Aguilera López, Andrés; Universidad de Sevilla. Departamento de Genética; European Research Council (ERC); Ministerio de Economía y Competitividad (MINECO). España
R loops are nucleic acid structures comprising an DNA-RNA hybrid and a displaced single-stranded DNA. These structures may occur transiently during transcription, playing essential biological functions. However, persistent R loops may become pathological as they are important drivers of genome instability and have been associated with human diseases. The mitochondrial degradosome is a functionally conserved complex from bacteria to human mitochondria. It is composed of the ATP-dependent RNA and DNA helicase SUV3 and the PNPase ribonuclease, playing a central role in mitochondrial RNA surveillance and degradation. Here we describe a new role for the mitochondrial degradosome in preventing the accumulation of pathological R loops in the mitochondrial DNA, in addition to preventing dsRNA accumulation. Our data indicate that, similar to the molecular mechanisms acting in the nucleus, RNA surveillance mechanisms in the mitochondria are crucial to maintain its genome integrity by counteracting pathological R-loop accumulation.
Human prefoldin modulates co-transcriptional pre-mRNA splicing
(Oxford University Press, 2021) Payán Bravo, Laura; Fontalva Ostio, Sara; Peñate Salas, Xenia; Cases, Ildefonso; Guerrero Martínez, José A.; Pareja Sánchez, Yerma; Odriozola Gil, Yosu; Lara, Esther; Jimeno González, Silvia; Suñé Negre, Carlos María; Muñoz Centeno, María de la Cruz; Reyes, José C.; Chávez de Diego, Sebastián; Universidad de Sevilla. Departamento de Genética
Prefoldin is a heterohexameric complex conserved from archaea to humans that plays a cochaperone role during the co-translational folding of actin and tubulin monomers. Additional functions of prefoldin have been described, including a positive contribution to transcription elongation and chromatin dynamics in yeast. Here we show that prefoldin perturbations provoked transcriptional alterations across the human genome. Severe pre-mRNA splicing defects were also detected, particularly after serum stimulation. We found impairment of co-transcriptional splicing during transcription elongation, which explains why the induction of long genes with a high number of introns was affected the most. We detected genome-wide prefoldin binding to transcribed genes and found that it correlated with the negative impact of prefoldin depletion on gene expression. Lack of prefoldin caused global decrease in Ser2 and Ser5 phosphorylation of the RNA polymerase II carboxy-terminal domain. It also reduced the recruitment of the CTD kinase CDK9 to transcribed genes, and the association of splicing factors PRP19 and U2AF65 to chromatin, which is known to depend on CTD phosphorylation. Altogether the reported results indicate that human prefoldin is able to act locally on the genome to modulate gene expression by influencing phosphorylation of elongating RNA polymerase II, and thereby regulating co-transcriptional splicing.
MipZ caps the plus-end of FtsZ polymers to promote their rapid disassembly
(NAS, 2022-12-09) Corrales Guerrero, Laura; Steinchen, Wieland; Ramm, Beatrice; Mücksch, Jonas; Rosum, Julia; Refes, Yacine; Heimerl, Thomas; Bange, Gert; Schwille, Petra; Thanbichler, Martin; Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular; Deutsche Forschungsgemeinschaft / German Research Foundation (DFG)
The spatiotemporal regulation of cell division is a fundamental issue in cell biology. Bacteria have evolved a variety of different systems to achieve proper division site placement. In many cases, the underlying molecular mechanisms are still incompletely understood. In this study, we investigate the function of the cell division regulator MipZ from Caulobacter crescentus, a P-loop ATPase that inhibits the polymerization of the treadmilling tubulin homolog FtsZ near the cell poles, thereby limiting the assembly of the cytokinetic Z ring to the midcell region. We show that MipZ interacts with FtsZ in both its monomeric and polymeric forms and induces the disassembly of FtsZ polymers in a manner that is not dependent but enhanced by the FtsZ GTPase activity. Using a combination of biochemical and genetic approaches, we then map the MipZ–FtsZ interaction interface. Our results reveal that MipZ employs a patch of surface-exposed hydrophobic residues to interact with the C-terminal region of the FtsZ core domain. In doing so, it sequesters FtsZ monomers and caps the (+)-end of FtsZ polymers, thereby promoting their rapid disassembly. We further show that MipZ influences the conformational dynamics of interacting FtsZ molecules, which could potentially contribute to modulating their assembly kinetics. Together, our findings show that MipZ uses a combination of mechanisms to control FtsZ polymerization, which may be required to robustly regulate the spatiotemporal dynamics of Z ring assembly within the cell.
Niche divergence and limits to expansion in the high polyploid Dianthus broteri complex
(Wiley, 2019) López Jurado, Javier; Mateos Naranjo, Enrique; Balao Robles, Francisco J.; Universidad de Sevilla. Departamento de Biología Vegetal y Ecología
Niche evolution in plant polyploids remains controversial and evidence for alternative patterns has been reported. Using the autopolyploid Dianthus broteri complex (2×, 4×, 6× and 12×) as a model, we aimed to integrate three scenarios – competitive exclusion, recurrent origins of cytotypes and niche filling – into a single framework of polyploid niche evolution. We hypothesized that high polyploids would tend to evolve towards extreme niches when low ploidy cytotypes have nearly filled the niche space. We used several ecoinformatics and phylogenetic comparative analyses to quantify differences in the ecological niche of each cytotype and to evaluate alternative models of niche evolution. Each cytotype in this complex occupied a distinct ecological niche. The distributions were mainly constrained by soil characteristics, temperature and drought stress imposed by the Mediterranean climate. Tetraploids had the highest niche breadth and overlap due to their multiple origins, whereas the higher ploidy cytotypes were found in different, restricted, nonoverlapping niches. Niche evolution analyses suggested a scenario with one niche optimum for each ploidy, including the two independent tetraploid lineages.Our results suggest that the fate of nascent polyploids could not be predicted without accounting for phylogenetic relatedness, recurrent origins or the niche occupied by ancestors.
Polyploidy promotes divergent evolution across the leaf economics spectrum and plant edaphic niche in the Dianthus broteri complex
(Wiley, 2022) López Jurado, Javier; Mateos Naranjo, Enrique; Balao Robles, Francisco J.; Universidad de Sevilla. Departamento de Biología Vegetal y Ecología; Ministerio de Ciencia, Innovación y Universidades (MICINN). España
The evolution of the leaf economics spectrum (LES) is known to be constrained by genetic relatedness but also promoted at small geographical and phylogenetic scales. In those cases, we hypothesized that polyploidy would play a prominent role as an outstanding source of functional divergence and adaptive potential. We registered leaf-level nutrient, water- and light-economy-related traits from the LES as well as edaphic properties in the four cytotypes of the autopolyploid Dianthus broteri complex (2×, 4×, 6× and 12×). We analysed the effect of ploidy level on the integration of the LES network, checked if concerted evolution occurred between LES and soil niche and tested the influence of phylogeny on the variables. Alternative evolutionary models for both sets of traits were compared. We found higher divergence of polyploids (especially 6× and 12×) compared to diploids in the LES and soil niche, but these traits are not coevolving. 6× and 12× showed opposite ecological strategies regarding resource use and higher uncoupling of the LES network. Early divergence of traits prevailed in both LES and edaphic niche (supported by better fitted evolutionary models with one optimum per cytotype), but post-polyploidization processes played an important role for the photochemical behaviour. Synthesis. Our results indicated shifts in ecological strategies across Dianthus broteri cytotypes and suggested a powerful role of polyploidy in overcoming constraints for the evolution of plant functional traits.
Quality-controlled ceramide-based GPI-anchored protein sorting into selective ER exit sites
(Elsevier, 2022) Rodríguez Gallardo, Sofía; Sabido Bozo, Susana; Ikeda, Atsuko; Araki, Misako; Okazaki, Kouta; Nakano, Miyako; Aguilera Romero, María Auxiliadora; Cortés Gómez, Alejandro; López Martín, Sergio; Waga, Miho; Nakano, Akihiko; Kurokawa, Kazuo; Muñiz Guinea, Manuel; Funato, Kouichi; Universidad de Sevilla. Departamento de Biología Celular; Society for the Promotion of Science. Japan; Agencia Estatal de Investigación. España; Junta de Andalucía; Universidad de Sevilla
Glycosylphosphatidylinositol-anchored proteins (GPI-APs) exit the endoplasmic reticulum (ER) through a specialized export pathway in the yeast Saccharomyces cerevisiae. We have recently shown that a very-long acyl chain (C26) ceramide present in the ER membrane drives clustering and sorting of GPI-APs into selective ER exit sites (ERES). Now, we show that this lipid-based ER sorting also involves the C26 ceramide as a lipid moiety of GPI-APs, which is incorporated into the GPI anchor through a lipid-remodeling process after protein attachment in the ER. Moreover, we also show that a GPI-AP with a C26 ceramide moiety is monitored by the GPI-glycan remodelase Ted1, which, in turn, is required for receptor-mediated export of GPI-APs. Therefore, our study reveals a quality-control system that ensures lipid-based sorting of GPI-APs into selective ERESs for differential ER export, highlighting the physiological need for this specific export pathway.
Reciprocity and Interaction Effectiveness in Generalised Mutualisms Among Free-living Species
(Wiley-Blackwell, 2023) Quintero Borrero, Elena; Rodríguez Sánchez, Francisco; Jordano Barbudo, Pedro D.; Universidad de Sevilla. Departamento de Biología Vegetal y Ecología; Agencia Estatal de Investigación. España; Universidad de Sevilla; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Fundación La Caixa
Mutualistic interactions among free-living species generally involve low-frequency interactions and highly asymmetric dependence among partners, yet our understanding of factors behind their emergence is still limited. Using individual-based interactions of a super-generalist fleshy-fruited plant with its frugivore assemblage, we estimated the Resource Provisioning Effectiveness (RPE) and Seed Dispersal Effectiveness (SDE) to assess the balance in the exchange of resources. Plants were highly dependent on a few frugivore species, while frugivores interacted with most individual plants, resulting in strong asymmetries of mutual dependence. Interaction effectiveness was mainly driven by interaction frequency. Despite highly asymmetric dependences, the strong reliance on quantity of fruit consumed determined high reciprocity in rewards between partners (i.e. higher energy provided by the plant, more seedlings recruited), which was not obscured by minor variations in the quality of animal or plant service. We anticipate reciprocity will emerge in low-intimacy mutualisms where the mutualistic outcome largely relies upon interaction frequency.
Regulation of bistability in the std fimbrial operon of Salmonella enterica by DNA adenine methylation and transcription factors HdfR, StdE and StdF
(Oxford Academic, 2019-09-05) García Pastor, Lucía; Sánchez Romero, María Antonia; Jakomin, Marcello; Puerta Fernández, Elena; Casadesús Pursals, Josep; Universidad de Sevilla. Departamento de Genética
Bistable expression of the Salmonella enterica std operon is controlled by an AND logic gate involving three transcriptional activators: the LysR-type factor HdfR and the StdE and StdF regulators encoded by the std operon itself. StdE activates transcription of the hdfR gene, and StdF activates std transcription together with HdfR. Binding of HdfR upstream of the std promoter is hindered by methylation of GATC sites located within the upstream activating sequence (UAS). Epigenetic control by Dam methylation thus antagonizes formation of the StdE-StdF-HdfR loop and tilts the std switch toward the StdOFF state. In turn, HdfR binding hinders methylation of the UAS, permitting activation of the StdE-StdF-HdfR loop and concomitant formation of StdON cells. Bistability is thus the outcome of competition between DNA adenine methylation and the StdE-StdF-HdfR activator loop.
Ribosomal protein L14 contributes to the early assembly of 60S ribosomal subunits in Saccharomyces cerevisiae
(Oxford University Press, 2018) Espinar Marchena, Francisco José; Rodríguez Galán, Olga; Fernández Fernández, José; Linnemann, Jan; Cruz Díaz, Jesús de la; Universidad de Sevilla. Departamento de Genética; Ministerio de Economía y Competitividad (MINECO). España; Deutsche Forschungsgemeinschaft / German Research Foundation (DFG)
The contribution of most ribosomal proteins to ribo- some synthesis has been quite well analysed in Sac- charomyces cerevisiae . However, few yeast riboso- mal proteins still await characterization. Herein, we show that L14, an essential 60S ribosomal protein, assembles in the nucleolus at an early stage into pre- 60S particles. Depletion of L14 results in a deficit in 60S subunits and defective processing of 27SA 2 and 27SA 3 to 27SB pre-rRNAs. As a result, 27S pre-rRNAs are subjected to turnover and export of pre-60S par- ticles is blocked. These phenotypes likely appear as the direct consequence of the reduced pre-60S par- ticle association not only of L14 upon its depletion but also of a set of neighboring ribosomal proteins located at the solvent interface of 60S subunits and the adjacent region surrounding the polypeptide exit tunnel. These pre-60S intermediates also lack some essential trans -acting factors required for 27SB pre- rRNA processing but accumulate practically all fac- tors required for processing of 27SA 3 pre-rRNA. We have also analysed the functional interaction be- tween the eukaryote-specific carboxy-terminal exten- sions of the neighboring L14 and L16 proteins. Our results indicate that removal of the most distal parts of these extensions cause slight translation alter- ations in mature 60S subunits.
Scutoids are a geometrical solution to three-dimensional packing of epithelia
(Nature Publishing Group, 2018) Gómez Gálvez, Pedro; Vicente Munuera, Pablo; Tagua Jáñez, Antonio; Forja Barbosa, Cristina; Castro Rodríguez, Ana María; Letrán, Marta; Grima Ruiz, Clara Isabel; Bermúdez Gallardo, Marina; Serrano Pérez-Higueras, Óscar; Márquez Pérez, Alberto; Escudero Cuadrado, Luis María; ; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Matemática Aplicada I (ETSII); Ministerio de Ciencia y Tecnología (MCYT). España
As animals develop, tissue bending contributes to shape the organs into complex three-dimensional structures. However, the architecture and packing of curved epithelia remains largely unknown. Here we show by means of mathematical modelling that cells in bent epithelia can undergo intercalations along the apico-basal axis. This phenomenon forces cells to have different neighbours in their basal and apical surfaces. As a consequence, epithelial cells adopt a novel shape that we term “scutoid”. The detailed analysis of diverse tissues confirms that generation of apico-basal intercalations between cells is a common feature during morphogenesis. Using biophysical arguments, we propose that scutoids make possible the minimization of the tissue energy and stabilize three-dimensional packing. Hence, we conclude that scutoids are one of nature's solutions to achieve epithelial bending. Our findings pave the way to understand the three-dimensional organization of epithelial organs.
Soil phenanthrene phytoremediation capacity in bacteria-assisted Spartina densiflora
(Elsevier, 2019-10-30) Mesa Marín, Jennifer; Barcia Piedras, José María; Mateos Naranjo, Enrique; Cox Meana, Lucía; Real Ojeda, Miguel; Pérez Romero, Jesús Alberto; Navarro de la Torre, Salvadora; Rodríguez Llorente, Ignacio David; Pajuelo Domínguez, Eloísa; Parra Martín, Raquel; Redondo Gómez, Susana; Universidad de Sevilla. Departamento de Biología Vegetal y Ecología; Universidad de Sevilla. Departamento de Microbiología y Parasitología; Ministerio de Economía y Competitividad (MINECO). España; Ministerio de Educación, Cultura y Deporte (MECD). España
Polycyclic aromatic hydrocarbons (PAH) have become a threat for the conservation of wetlands worldwide. The halophyte Spartina densiflora has shown to be potentially useful for soil phenanthrene phytoremediation, but no studies on bacteria-assisted hydrocarbon phytoremediation have been carried out with this halophyte. In this work, three phenanthrene-degrading endophytic bacteria were isolated from S. densiflora tissues and used for plant inoculation. Bacterial bioaugmentation treatments slightly improved S. densiflora growth, photosynthetic and fluorescence parameters. But endophyte-inoculated S. densiflora showed lower soil phenanthrene dissipation rates than non-inoculated S. densiflora (30% below) or even bulk soil (23% less). Our work demonstrates that endophytic inoculation on S. densiflora under greenhouse conditions with the selected PAH-degrading strains did not significantly increase inherent phenanthrene soil dissipation capacity of the halophyte. It would therefore be advisable to provide effective follow-up of bacterial colonization, survival and metabolic activity during phenanthrene soil phytoremediation.
SUMO-activated Target Traps (SATTs) Enable the Identification of a Comprehensive E3-specific SUMO Proteome
(American Association for the Advancement of Science, 2023) Salas Lloret, Daniel; Jansen, Nicolette S.; Nagamalleswari, Easa; van der Meulen, Coen; Gracheva, Ekaterina; de Ru, Arnoud H.; Otte, H. Anne Marie; van Veelen, Peter A.; Pichler, Andrea; Goedhart, Joachim; Vertegaal, Alfred C.O.; González Prieto, Román; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Dutch Cancer Society; European Research Council (ERC); Dutch Research Council; Swiss National Science Foundation (SNFS)
Ubiquitin and ubiquitin-like conjugation cascades consist of dedicated E1, E2, and E3 enzymes with E3s providing substrate specificity. Mass spectrometry–based approaches have enabled the identification of more than 6500 SUMO2/3 target proteins. The limited number of SUMO E3s provides the unique opportunity to systematically study E3 substrate wiring. We developed SUMO-activated target traps (SATTs) and systematically identified substrates for eight different SUMO E3s, PIAS1, PIAS2, PIAS3, PIAS4, NSMCE2, ZNF451, LAZSUL (ZNF451-3), and ZMIZ2. SATTs enabled us to identify 427 SUMO1 and 961 SUMO2/3 targets in an E3-specific manner. We found pronounced E3 substrate preference. Quantitative proteomics enabled us to measure substrate specificity of E3s, quantified using the SATT index. Furthermore, we developed the Polar SATTs web-based tool to browse the dataset in an interactive manner. Overall, we uncover E3-to-target wiring of 1388 SUMO substrates, highlighting unique and overlapping sets of substrates for eight different SUMO E3 ligases.
The SWI/SNF chromatin remodeling complex helps resolve R-loop-mediated transcription–replication conflicts
(Springer Nature, 2021) Bayona Feliu, Aleix; Barroso Ceballos, Sonia Inés; Muñoz Sánchez, Sergio; Aguilera López, Andrés; Universidad de Sevilla. Departamento de Genética
ATP-dependent chromatin remodelers are commonly mutated in human cancer. Mammalian SWI/SNF complexes comprise three conserved multisubunit chromatin remodelers (cBAF, ncBAF and PBAF) that share the BRG1 (also known as SMARCA4) subunit responsible for the main ATPase activity. BRG1 is the most frequently mutated Snf2-like ATPase in cancer. In the present study, we have investigated the role of SWI/SNF in genome instability, a hallmark of cancer cells, given its role in transcription, DNA replication and DNA-damage repair. We show that depletion of BRG1 increases R-loops and R-loop-dependent DNA breaks, as well as transcription–replication (T-R) conflicts. BRG1 colocalizes with R-loops and replication fork blocks, as determined by FANCD2 foci, with BRG1 depletion being epistatic to FANCD2 silencing. Our study, extended to other components of SWI/SNF, uncovers a key role of the SWI/SNF complex, in particular cBAF, in helping resolve R-loop-mediated T-R conflicts, thus, unveiling a new mechanism by which chromatin remodeling protects genome integrity.
VEGF is an essential retrograde trophic factor for motoneurons
(National Academy of Sciences, 2022) Martín Calvo, Paula; García Hernández, Rosendo Miguel; Rodríguez de la Cruz, Rosa María; Pastor Loro, Ángel Manuel; Universidad de Sevilla. Departamento de Fisiología; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
VEGF was initially discovered due to its angiogenic activity and therefore named "vascular endothelial growth factor."However, its more recently discovered neurotrophic activity may be evolutionarily more ancient. Our previous work showed that all the changes produced by axotomy on the firing activity and synaptic inputs of abducens motoneurons were completely restored after VEGF administration. Therefore, we hypothesized that the lack of VEGF delivered by retrograde transport from the periphery should also affect the physiology of otherwise intact abducens motoneurons. For VEGF retrograde blockade, we chronically applied a neutralizing VEGF antibody to the lateral rectus muscle. Recordings of extracellular single-unit activity and eye movements were made in alert cats before and after the application of the neutralizing antibody. Our data revealed that intact, noninjured abducens motoneurons retrogradely deprived of VEGF exhibited noticeable changes in their firing pattern. There is a general decrease in firing rate and a significant reduction in eye position and eye velocity sensitivity (i.e., a decrease in the tonic and phasic components of their discharge, respectively). Moreover, by means of confocal immunocytochemistry, motoneurons under VEGF blockade showed a marked reduction in the density of afferent synaptic terminals contacting with their cell bodies. Altogether, the present findings demonstrate that the lack of retrogradely delivered VEGF renders abducens motoneurons into an axotomy-like state. This indicates that VEGF is an essential retrograde factor for motoneuronal synaptic drive and discharge activity.

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