Artículos (Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER))

URI permanente para esta colecciónhttps://hdl.handle.net/11441/11090

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The nucleolus: Coordinating Stress Response and Genomic Stability
(Elsevier, 2024) González Arzola, Katiuska; Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular
The perception that the nucleoli are merely the organelles where ribosome biogenesis occurs is challenged. Only around 30 % of nucleolar proteins are solely involved in producing ribosomes. Instead, the nucleolus plays a critical role in controlling protein trafficking during stress and, according to its dynamic nature, undergoes continuous protein exchange with nucleoplasm under various cellular stressors. Hence, the concept of nucleolar stress has evolved as cellular insults that disrupt the structure and function of the nucleolus. Considering the emerging role of this organelle in DNA repair and the fact that rDNAs are the most fragile genomic loci, therapies targeting the nucleoli are increasingly being developed. Besides, drugs that target ribosome synthesis and induce nucleolar stress can be used in cancer therapy. In contrast, agents that regulate nucleolar activity may be a potential treatment for neurodegeneration caused by abnormal protein accumulation in the nucleolus. Here, I explore the roles of nucleoli beyond their ribosomal functions, highlighting the factors triggering nucleolar stress and their impact on genomic stability.
Inadequate control of thyroid hormones sensitizes to hepatocarcinogenesis and unhealthy aging
(Impact Journals LLC, 2019-09) López Noriega, Livia; Capilla González, Vivian; Cobo Vuilleumier, Nadia; Martin Vázquez, Eugenia; Lorenzo, Petra I.; Martínez Force, Enrique; Soriano Navarro, Mario; García Fernández, María; Romero Zerbo, Silvana Y.; Díaz Contreras, Irene; Gauthier, Benoit R.; Martín Montalvo, Alejandro; Universidad de Sevilla. Departamento de Biología Celular
An inverse correlation between thyroid hormone levels and longevity has been reported in several species and reduced thyroid hormone levels have been proposed as a biomarker for healthy aging and metabolic fitness. However, hypothyroidism is a medical condition associated with compromised health and reduced life expectancy. Herein, we show, using wild-type and the Pax8 ablated model of hypothyroidism in mice, that hyperthyroidism and severe hypothyroidism are associated with an overall unhealthy status and shorter lifespan. Mild hypothyroid Pax8 +/- mice were heavier and displayed insulin resistance, hepatic steatosis and increased prevalence of liver cancer yet had normal lifespan. These pathophysiological conditions were precipitated by hepatic mitochondrial dysfunction and oxidative damage accumulation. These findings indicate that individuals carrying mutations on PAX8 may be susceptible to develop liver cancer and/or diabetes and raise concerns regarding the development of interventions aiming to modulate thyroid hormones to promote healthy aging or lifespan in mammals.
Human DNA Topoisomerase I Poisoning Causes R Loop-mediated Genome Instability Attenuated by Transcription Factor IIS
(American Association for the Advancement of Science, 2024) Duardo, Renée C.; Marinello, Jessica; Russo, Marco; Morelli, Sara; Pepe, Simona; Guerra, Federico; Gómez González, Belén; Aguilera López, Andrés; Capranico, Giovanni; Universidad de Sevilla. Departamento de Genética; Associazione italiana per la Ricerca sul cancro (AIRC). Italy; Ministry of University and Research. Rome, Italy; Ministerio de Ciencia e Innovación (MICIN). España; European Research Council (ERC); European Union (UE)
DNA topoisomerase I can contribute to cancer genome instability. During catalytic activity, topoisomerase I forms a transient intermediate, topoisomerase I-DNA cleavage complex (Top1cc) to allow strand rotation and duplex relaxation, which can lead to elevated levels of DNA-RNA hybrids and micronuclei. To comprehend the underlying mechanisms, we have integrated genomic data of Top1cc-triggered hybrids and DNA double-strand breaks (DSBs) shortly after Top1cc induction, revealing that Top1ccs increase hybrid levels with different mechanisms. DSBs are at highly transcribed genes in early replicating initiation zones and overlap with hybrids downstream of accumulated RNA polymerase II (RNAPII) at gene 5'-ends. A transcription factor IIS mutant impairing transcription elongation further increased RNAPII accumulation likely due to backtracking. Moreover, Top1ccs can trigger micronuclei when occurring during late G1 or early/mid S, but not during late S. As micronuclei and transcription-replication conflicts are attenuated by transcription factor IIS, our results support a role of RNAPII arrest in Top1cc-induced transcription-replication conflicts leading to DSBs and micronuclei.
Histone variant H2A.Z is needed for efficient transcription-coupled NER and genome integrity in UV challenged yeast cells
(Public Library of Science, 2024-09-10) Gaillard, Hélène; Ciudad, Toni; Aguilera López, Andrés; Wellinger, Ralf Erik; Universidad de Sevilla. Departamento de Genética; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Junta de Andalucía; Universidad de Sevilla; Ministerio de Economía y Competitividad (MINECO). España
The genome of living cells is constantly challenged by DNA lesions that interfere with cellular processes such as transcription and replication. A manifold of mechanisms act in concert to ensure adequate DNA repair, gene expression, and genome stability. Bulky DNA lesions, such as those induced by UV light or the DNA-damaging agent 4-nitroquinoline oxide, act as transcriptional and replicational roadblocks and thus represent a major threat to cell metabolism. When located on the transcribed strand of active genes, these lesions are handled by transcription-coupled nucleotide excision repair (TC-NER), a yet incompletely understood NER sub-pathway. Here, using a genetic screen in the yeast Saccharomyces cerevisiae, we identified histone variant H2A.Z as an important component to safeguard transcription and DNA integrity following UV irradiation. In the absence of H2A.Z, repair by TC-NER is severely impaired and RNA polymerase II clearance reduced, leading to an increase in double-strand breaks. Thus, H2A.Z is needed for proficient TC-NER and plays a major role in the maintenance of genome stability upon UV irradiation.
Spontaneous deamination of cytosine to uracil is biased to the non-transcribed DNA strand in yeast
(Elsevier, 2023-06) Williams, Jonathan D.; Zhu, Demi; García Rubio, María Luisa; Shaltz, Samantha; Aguilera López, Andrés; Jinks-Robertson, Sue; Universidad de Sevilla. Departamento de Genética; National Institutes of Health. United States; Ministerio de Ciencia e Innovación (MICIN). España
Transcription in Saccharomyces cerevisiae is associated with elevated mutation and this partially reflects enhanced damage of the corresponding DNA. Spontaneous deamination of cytosine to uracil leads to CG>TA mutations that provide a strand-specific read-out of damage in strains that lack the ability to remove uracil from DNA. Using the CAN1 forward mutation reporter, we found that C>T and G>A mutations, which reflect deamination of the non-transcribed and transcribed DNA strands, respectively, occurred at similar rates under low-transcription conditions. By contrast, the rate of C>T mutations was 3-fold higher than G>A mutations under high-transcription conditions, demonstrating biased deamination of the non-transcribed strand (NTS). The NTS is transiently single-stranded within the ∼15 bp transcription bubble, or a more extensive region of the NTS can be exposed as part of an R-loop that can form behind RNA polymerase. Neither the deletion of genes whose products restrain R-loop formation nor the over-expression of RNase H1, which degrades R-loops, reduced the biased deamination of the NTS, and no transcription-associated R-loop formation at CAN1 was detected. These results suggest that the NTS within the transcription bubble is a target for spontaneous deamination and likely other types of DNA damage.
PLK1 Regulates CtIP and DNA2 Interplay in Long-range DNA end Resection.
(Cold Spring Harbor Laboratory Press, 2023) Ceppi, Ilaria; Cannavo, Elda; Bret, Helene; Camarillo Daza, María Rosa; Vivalda, Francesca; Thakur, Roshan Singh; Romero Franco, Amador; Sartori, Alessandro A.; Huertas Sánchez, Pablo; Guerois, Raphael; Cejka, Petr; Universidad de Sevilla. Departamento de Genética; European Research Council (ERC); Swiss National Science Foundation (SNFS); Ministerio de Ciencia e Innovación (MICIN). España; French government
DNA double-strand break (DSB) repair is initiated by DNA end resection. CtIP acts in short-range resection to stimulate MRE11–RAD50–NBS1 (MRN) to endonucleolytically cleave 5′-terminatedDNAto bypass protein blocks. CtIP also promotes the DNA2 helicase–nuclease to accelerate long-range resection downstream from MRN. Here, using AlphaFold2, we identified CtIP-F728E-Y736E as a separation-of-function mutant that is still proficient in conjunction with MRN but is not able to stimulate ssDNA degradation by DNA2. Accordingly, CtIP-F728E-Y736E impairs physical interaction with DNA2. Cellular assays revealed that CtIP-F728E-Y736E cells exhibit reduced DSB-dependent chromatin-bound RPA, impaired long-range resection, and increased sensitivity to DSB-inducing drugs. Previously, CtIP was shown to be targeted by PLK1 to inhibit long-range resection, yet the underlying mechanism was unclear. We show that the DNA2-interacting region in CtIP includes the PLK1 target site at S723. The integrity of S723 in CtIP is necessary for the stimulation of DNA2, and phosphorylation of CtIP by PLK1 in vitro is consequently inhibitory, explaining why PLK1 restricts long-range resection. Our data support a model in which CDK-dependent phosphorylation of CtIP activates resection by MRN in S phase, and PLK1-mediated phosphorylation of CtIP disrupts CtIP stimulation of DNA2 to attenuate long-range resection later at G2/M.
EXO1 and DNA2-mediated ssDNA gap expansion is essential for ATR activation and to maintain viability in BRCA1-deficient cells
(Oxford University Press, 2024-06-24) García Rodríguez, Néstor; Domínguez García, Iria; Domínguez Pérez, María del Carmen; Huertas Sánchez, Pablo; Universidad de Sevilla. Departamento de Genética; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España
DNA replication faces challenges from DNA lesions originated from endogenous or exogenous sources of stress, leading to the accumulation of single-stranded DNA (ssDNA) that triggers the activation of the ATR checkpoint response. To complete genome replication in the presence of damaged DNA, cells employ DNA damage tolerance mechanisms that operate not only at stalled replication forks but also at ssDNA gaps originated by repriming of DNA synthesis downstream of lesions. Here, we demonstrate that human cells accumulate post-replicative ssDNA gaps following replicative stress induction. These gaps, initiated by PrimPol repriming and expanded by the long-range resection factors EXO1 and DNA2, constitute the principal origin of the ssDNA signal responsible for ATR activation upon replication stress, in contrast to stalled forks. Strikingly, the loss of EXO1 or DNA2 results in synthetic lethality when combined with BRCA1 deficiency, but not BRCA2. This phenomenon aligns with the observation that BRCA1 alone contributes to the expansion of ssDNA gaps. Remarkably, BRCA1-deficient cells become addicted to the overexpression of EXO1, DNA2 or BLM. This dependence on long-range resection unveils a new vulnerability of BRCA1-mutant tumors, shedding light on potential therapeutic targets for these cancers.
Prevalence of dens invaginatus assessed by cbct: systematic review and meta-analysis
(Medicina Oral S.L, 2022) González-Mancilla, Sara; Montero Miralles, Paloma; Sauco Márquez, Juan José; Areal Quecuty, Victoria; Cabanillas Balsera, Daniel; Segura Egea, Juan José; ; Universidad de Sevilla. Departamento de Estomatología; Instituto de Biomedicina de Sevilla (IBIS); Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER)
Background: Dens invaginatus is a developmental dental anomaly resulting from an invagination of dental tissues folding from the outer surface towards dental pulp. The aim of this systematic review and meta-analysis was to determine the prevalence of dens invaginatus using cone beam computed tomography (CBCT). Material and Methods: A systematic review was conducted following PRISMA statements. The research question was: What is the prevalence of dens invaginatus in the adult population assessed by CBCT? The MeSH terms were used to search articles published in the electronic database PubMed. Studies were selected considering predeter mined eligibility criteria. The Robins-I tool developed by Cochrane was used to assess methodological quality and risk of bias. Results: Four studies were included in this systematic review, including 2009 CBCT images. The overall preva lence of dens invaginatus was 9.0% (95% CI = 7.2 – 10.8%; p < 0.001). Three studies were considered of low risk of bias. Conclusions: The results of this systematic review and meta-analysis show that prevalence of dens invaginatus using CBCT was higher than previous estimations carried out with conventional radiographs. Therefore, an early identification and a correct management of invaginated teeth is essential for improving the prognosis of these teeth. It can be concluded that teeth with dens invaginatus should always be studied using CBCT
Prevalence of root canal treatments among diabetic patients: systematic review and meta-analysis
(Mdpi, 2023) León-López, María; Cabanillas Balsera, Daniel; Martín González, Jenifer; Díaz Flores, Víctor; Areal Quecuty, Victoria; Crespo Gallardo, Isabel; Montero Miralles, Paloma; Segura Egea, Juan José; Universidad de Sevilla. Departamento de Estomatología; Instituto de Biomedicina de Sevilla (IBIS); Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER)
(1) Apical periodontitis (AP) is the inflammatory response of the periapical tissue to bacterial antigens and toxins arriving from inside the root canal after pulp necrosis. To control AP, it is necessary to interrupt the passage of antigens from the root canal to the periapex, which is achieved via a root canal treatment (RCT), which is the indicated endodontic therapy in cases of AP. The prevalence of root-filled teeth (RFT) is an indicator of the frequency of endodontic infections and the degree of dental care. Diabetes is associated with AP and has been identified as the main prognostic factor in RCT. The aim of this study was to carry out a systematic review with meta analysis answering the following question: What is the prevalence of RFT among diabetic patients? (2) This study was conducted following the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) guidelines 2020. A literature search was undertaken without limits on time All studies reporting the prevalence of RFT among diabetic patients via radiographic examination; both panoramic and periapical radiographs were included. Meta-analyses were calculated with Open Meta Analyst software. The main outcome variable was the prevalence of RFT, calculated as the total number of RFT divided by the total number of teeth, which is expressed as a percentage. As a secondary outcome variable, the prevalence of diabetic patients with at least one RFT, expressed as a percentage, was also calculated. The quality of evidence of the included studies was analyzed according to the guidelines provided by the Centre for Evidence-Based Medicine in Oxford. The risk of bias was assessed using the Newcastle–Ottawa Scale, which was adapted for cross-sectional studies. To estimate the variance and heterogeneity amongst the trials, the Higgings I2 test was employed. (3) Eight studies fulfilled the inclusion criteria. Four studies were classified as having a high risk of bias, and four were classified as having a moderate risk of bias. The prevalence of RFT was estimated for 37,922 teeth and 1532 diabetic patients. The overall calculated prevalence of RFT among diabetic patients was 5.5% (95% CI = 4.1–6.9%; p < 0.001). The percentage of diabetics who had at least one RFT was42.7% (95% CI =23.9–61.4%; p < 0.001). (4) This systematic review and meta-analysis concluded that the prevalence of RFT among diabetic patients is 5.5%. More than 40% of diabetics have at least one RFT. In daily clinics, dentists should suspect that patients are undiagnosed diabetics when multiple RCT failures are observed in the same patient.
UBE2D3 Facilitates NHEJ by Orchestrating ATM Signalling through Multi-level Control of RNF168
(Springer Nature, 2024) Yalçin, Zeliha; Lam, Shiu Yeung; Peuscher, Marieke H.; van der Torre, Jaco; Zhu, Sha; Iyengar, Prasanna V.; Salas Lloret, Daniel; de Krijger, Inge; Moatti, Nathalie; van der Lugt, Ruben; González Prieto, Román; Jacobs, Jacqueline J.L.; Universidad de Sevilla. Departamento de Biología Celular
Maintenance of genome integrity requires tight control of DNA damage response (DDR) signalling and repair, with phosphorylation and ubiquitination representing key elements. How these events are coordinated to achieve productive DNA repair remains elusive. Here we identify the ubiquitin-conjugating enzyme UBE2D3 as a regulator of ATM kinase-induced DDR that promotes non-homologous end-joining (NHEJ) at telomeres. UBE2D3 contributes to DDR-induced chromatin ubiquitination and recruitment of the NHEJ-promoting factor 53BP1, both mediated by RNF168 upon ATM activation. Additionally, UBE2D3 promotes NHEJ by limiting RNF168 accumulation and facilitating ATM-mediated phosphorylation of KAP1-S824. Mechanistically, defective KAP1-S824 phosphorylation and telomeric NHEJ upon UBE2D3-deficiency are linked to RNF168 hyperaccumulation and aberrant PP2A phosphatase activity. Together, our results identify UBE2D3 as a multi-level regulator of NHEJ that orchestrates ATM and RNF168 activities. Moreover, they reveal a negative regulatory circuit in the DDR that is constrained by UBE2D3 and consists of RNF168- and phosphatase-mediated restriction of KAP1 phosphorylation.
Physical interactions between specifically regulated subpopulations of the MCM and RNR complexes prevent genetic instability
(Public Library of Science, 2024-05-22) Yáñez Vilches, Aurora; Romero, Antonia M.; Barrientos Moreno, Marta; Cruz, Esther; González Prieto, Román; Sharma, Sushma; Vertegaal, Alfred C.O.; Prado, Félix; Universidad de Sevilla. Departamento de Biología Celular
The helicase MCM and the ribonucleotide reductase RNR are the complexes that provide the substrates (ssDNA templates and dNTPs, respectively) for DNA replication. Here, we demonstrate that MCM interacts physically with RNR and some of its regulators, including the kinase Dun1. These physical interactions encompass small subpopulations of MCM and RNR, are independent of the major subcellular locations of these two complexes, augment in response to DNA damage and, in the case of the Rnr2 and Rnr4 subunits of RNR, depend on Dun1. Partial disruption of the MCM/RNR interactions impairs the release of Rad52 -but not RPA-from the DNA repair centers despite the lesions are repaired, a phenotype that is associated with hypermutagenesis but not with alterations in the levels of dNTPs. These results suggest that a specifically regulated pool of MCM and RNR complexes plays noncanonical roles in genetic stability preventing persistent Rad52 centers and hypermutagenesis.
Roles of Extracellular Vesicles Associated Non-coding RNAs in Diabetes Mellitus
(Frontiers Media SA, 2022) Gauthier, B.R.; Cobo Vuilleumier, Nadia; López Noriega, Livia; Universidad de Sevilla. Departamento de Biología Celular; Junta de Andalucía; Ministerio de Economía y Competitividad (MINECO). España; Juvenile Diabetes Research Foundation (JDRF). USA
Extracellular vesicles (EVs), especially exosomes (50 to 150 nm), have been shown to play important roles in a wide range of physiological and pathological processes, including metabolic diseases such as Diabetes Mellitus (DM). In the last decade, several studies have demonstrated how EVs are involved in cell-to-cell communication. EVs are enriched in proteins, mRNAs and non-coding RNAs (miRNAs, long non-coding RNAs and circRNAS, among others) which are transferred to recipient cells and may have a profound impact in either their survival or functionality. Several studies have pointed out the contribution of exosomal miRNAs, such as miR-l42-3p and miR-26, in the development of Type 1 and Type 2 DM (T1DM and T2DM), respectively. In addition, some miRNA families such as miR-let7 and miR-29 found in exosomes have been associated with both types of diabetes, suggesting that they share common etiological features. The knowledge about the role of exosomal long non-coding RNAs in this group of diseases is more immature, but the exosomal lncRNA MALAT1 has been found to be elevated in the plasma of individuals with T2DM, while more than 169 lncRNAs were reported to be differentially expressed between healthy donors and people with T1DM. Here, we review the current knowledge about exosomal non-coding RNAs in DM and discuss their potential as novel biomarkers and possible therapeutic targets.
Physical Forces and Transient Nuclear Envelope Rupture During Metastasis: The Key for Success?
(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Gauthier, B.R.; Lorenzo, P.I.; Comaills, Valentine; Universidad de Sevilla. Departamento de Biología Celular; Asociación Española Contra el Cáncer (AECC); Junta de Andalucía; Ministerio de Economía y Competitividad (MINECO). España; Juvenile Diabetes Research Foundation (JDRF). USA
During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects.
NR5A2/LRH-1 Regulates the PTGS2-PGE2-PTGER1 Pathway Contributing to Pancreatic Islet Survival and Function
(Elsevier, 2022) Martin Vázquez, Eugenia; Cobo Vuilleumier, Nadia; Araujo Legido, Raquel; Marín Cañas, Sandra; Nola, Emanuele; Dorronsoro, Akaitz; López Bermudo, Lucía; Crespo, Alejandra; Romero Zerbo, Silvana Y.; Comaills, Valentine; Gauthier, Benoit R.; Universidad de Sevilla. Departamento de Biología Celular; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España; Juvenile Diabetes Research Foundation. USA; Instituto de Salud Carlos III
LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglyce- mia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection. LRH-1 ablation within developing beta cells impeded beta cell proliferation, correlating with mouse growth retardation, weight loss, and hypoglycemia leading to lethality. LRH-1 deletion in adult beta cells abolished the BL001 antidiabetic action, correlating with beta cell destruction and blunted Ptgs2 induction. Islet PTGS2 inactivation led to reduced PGE 2 levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome c release and cleaved-PARP. The PTGER1 antagonist—ONO-8130—negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE 2 /PTGER1 signaling axis as a key pathway medi- ating BL001 survival properties.
The PTGS2/COX2-PGE2 Signaling Cascade in Inflammation: Pro or Anti? A Case Study with Type 1 Diabetes Mellitus
(Ivyspring International Publisher, 2023) Martín Vázquez, Eugenia; Cobo Vuilleumier, Nadia; López Noriega, Livia; Lorenzo, Petra I.; Gauthier, Benoit R.; Universidad de Sevilla. Departamento de Biología Celular; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España; Juvenile Diabetes Research Foundation. USA
Prostaglandins are lipid mediators involved in physiological processes, such as constriction or dilation of blood vessels, but also pathophysiological processes, which include inflammation, pain and fever. They are produced by almost all cell types in the organism by activation of Prostaglandin endoperoxide synthases/Cyclooxygenases. The inducible Prostaglandin Endoperoxide Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) plays an important role in pathologies associated with inflammatory signaling. The main product derived from PTGS2/COX2 expression and activation is Prostaglandin E2 (PGE2), which promotes a wide variety of tissue-specific effects, pending environmental inputs. One of the major sources of PGE2 are infiltrating inflammatory cells - the production of this molecule increases drastically in damaged tissues. Immune infiltration is a hallmark of type 1 diabetes mellitus, a multifactorial disease that leads to autoimmune-mediated pancreatic beta cell destruction. Controversial effects for the PTGS2/COX2-PGE2 signaling cascade in pancreatic islet cells subjected to diabetogenic conditions have been reported, allocating PGE2 as both, cause and consequence of inflammation. Herein, we review the main effects of this molecular pathway in a tissue-specific manner, with a special emphasis on beta cell mass protection/destruction and its potential role in the prevention or development of T1DM. We also discuss strategies to target this pathway for future therapies.
Metabolic Reprogramming by Acly Inhibition Using SB-204990 Alters Glucoregulation and Modulates Molecular Mechanisms Associated with Aging
(Springer Nature, 2023) Sola García, Alejandro; Cáliz Molina, María Ángeles; Espadas, Isabel; Petr, Michael; Panadero Morón, Concepción; González Morán, Daniel; Martín Vázquez, María Eugenia; Narbona Pérez, Álvaro Jesús; López Noriega, Livia; Martínez Corrales, Guillermo; Martín Montalvo, Alejandro; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Economía y Competitividad (MINECO). España; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Consejo Superior de Investigaciones Científicas (CSIC); Nordea Foundation. Dinamarca; Novo Nordisk Foundation. Dinamarca; Lundbeck Foundation. Dinamarca; Ministry of Higher Education and Science of Denmark; Instituto de Salud Carlos III
ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.
Enzyme-Responsive Zr-Based Metal-Organic Frameworks for Controlled Drug Delivery: Taking Advantage of Clickable PEG-Phosphate Ligands
(American Chemical Society, 2023) Carrillo Carrión, Carolina; Comaills, Valentine; Visiga, Ana M.; Gauthier, Benoit R.; Khiar, Noureddine; Universidad de Sevilla. Departamento de Biología Celular; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía; Asociación Española Contra el Cáncer; Marie Sklodowska-Curie Individual Fellowship; European Cooperation in Science and Technology (COST)
We report for the first time the controlled drug release from a nanoscale Zr-based metal-organic framework (MOF), UiO-66, in the presence of the enzyme alkaline phosphatase (ALP). This unprecedented reactivity was possible thanks to the prior functionalization of the MOF with N3-PEG-PO3 ligands, which were designed for three specific aims: (1) to impart colloidal stability in phosphate-containing media; (2) to endow the MOF with multifunctionality thanks to azide groups for the covalent attachment of an imaging agent by click-chemistry; and (3) to confer stimuli-responsive properties, specifically the selective release of doxorubicin triggered by the enzymatic activity of ALP. Cell studies revealed that the functionalization of the MOF with N3-(PEG)20-PO3 ligands improved their intracellular stability and led to a sustained drug release compared to the bare MOF. More importantly, an enhanced drug release was observed in cells with higher expression of ALP genes (HeLa versus MDA-MB-231 and MCF7), confirming the ALP-responsiveness of the system inside living cells.
Expression of human RECQL5 in Saccharomyces cerevisiae causes transcription defects and transcription-associated genome instability
(Springer Nature, 2024-05-26) Lafuente Barquero, Juan Francisco; Svejstrup, Jesper Q.; Luna Varo, Rosa María; Aguilera López, Andrés; Universidad de Sevilla. Departamento de Genética; Ministerio de Ciencia e Innovación (MICIN). España; European Research Council (ERC); Novo Nordisk Foundation; Danish National Research Foundation
RECQL5 is a member of the conserved RecQ family of DNA helicases involved in the maintenance of genome stability that is specifically found in higher eukaryotes and associates with the elongating RNA polymerase II. To expand our understanding of its function we expressed human RECQL5 in the yeast Saccharomyces cerevisiae, which does not have a RECQL5 ortholog. We found that RECQL5 expression leads to cell growth inhibition, increased genotoxic sensitivity and transcription-associated hyperrecombination. Chromatin immunoprecipitation and transcriptomic analysis of yeast cells expressing human RECQL5 shows that this is recruited to transcribed genes and although it causes only a weak impact on gene expression, in particular at G + C-rich genes, it leads to a transcription termination defect detected as readthrough transcription. The data indicate that the interaction between RNAPII and RECQL5 is conserved from yeast to humans. Unexpectedly, however, the RECQL5-ID mutant, previously shown to have reduced the association with RNAPII in vitro, associates with the transcribing polymerase in cells. As a result, expression of RECQL5-ID leads to similar although weaker phenotypes than wild-type RECQL5 that could be transcription-mediated. Altogether, the data suggests that RECQL5 has the intrinsic ability to function in transcription-dependent and independent genome dynamics in S. cerevisiae.
BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis
(Nature Research, 2024-05-20) Salas Lloret, Daniel; García Rodríguez, Néstor; Soto Hidalgo, Emily; González Vinceiro, Lourdes; Espejo Serrano, Carmen; Giebel, Lisanne; Huertas Sánchez, Pablo; González Prieto, Román; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Genética; Junta de Andalucía; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Agencia Estatal de Investigación. España; European Union (UE)
Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial. Here, we observe that the BRCA1/BARD1 ubiquitin E3 activity is not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identify substrates for BRCA1/BARD1. We find that PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18. PCNA ubiquitination by BRCA1/BARD1 avoids the formation of ssDNA gaps during DNA replication and promotes continuous DNA synthesis. These results provide additional insight about the importance of BRCA1/BARD1 E3 activity in Homologous Recombination.
Sperm-contributed centrioles segregate stochastically into blastomeres of 4-cell stage Caenorhabditis elegans embryos
(Oxford University Press, 2023-03-29) Gönczy, Pierre; Romero Balestra, Fernando; Universidad de Sevilla. Departamento de Genética; Oficina de Programas de Infraestructura de Investigación. National Institutes of Health (NIH)
Whereas both sperm and egg contribute nuclear genetic material to the zygote in metazoan organisms, the inheritance of other cellular constituents is unequal between the 2 gametes. Thus, 2 copies of the centriole are contributed solely by the sperm to the zygote in most species. Centrioles can have a stereotyped distribution in some asymmetric divisions, but whether sperm-contributed centrioles are distributed in a stereotyped manner in the resulting embryo is not known. Here, we address this question in Caenorhabditis elegans using marked mating experiments, whereby the presence of the 2 sperm-contributed centrioles is monitored in the embryo using the stable centriolar component SAS-4::GFP, as well as GFP::SAS-7. Our analysis demonstrates that the distribution of sperm-contributed centrioles is stochastic in 4-cell stage embryos. Moreover, using sperm from zyg-1 mutant males that harbor a single centriole, we show that the older sperm-contributed centriole is likewise distributed stochastically in the resulting embryo. Overall, we conclude that, in contrast to the situation during some asymmetric cell divisions, centrioles contributed by the male germ line are distributed stochastically in embryos of C. elegans

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