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Background Mandibular hypoplasia, Deafness, Progeroid features, and Lipodystrophy (MDPL) syndrome is a very rare genetic disorder linked to variants in the POLD1 gene, which encodes the catalytic subunit of DNA polymerase delta, a key enzyme involved in DNA replication and repair. Most patients carry a recurrent in frame deletion (p.Ser605del) within the active site of the p125 subunit. Despite its rarity, understanding the functional consequences of the Ser605del variant has broad implications for aging-related diseases and genome stability. Methods We combined structural modelling, molecular dynamics simulations, and protein–protein interaction (PPIs) analyses to evaluate the impact of Ser605del in the catalytic activity of DNA polymerase delta. Bioinformatic tools were applied to characterize its interaction network. RT-q PCR and Western Blot were performed to assess expression levels of POLD1, TRF1, and PARP1 in human dermal fibroblasts (HDFs) of three MDPL patients of different ages. Cells were monitored at different passages, both in basal condition and after damage by X irradiation. POLD1/TRF1 interaction was confirmed by immunoprecipitation analyses. Results Using molecular docking, molecular dynamics simulations and thermodynamic analyses, we found that Ser605del affects the DNA-binding site, impairing dTTP binding. The deletion alters short linear motifs involved in protein–protein interactions (PPIs), allowing the acquisition of a F/Y-X-L-X-P (FSLYP) consensus sequence with TRF1, a telomeric protein. In silico analyses highlighted a stronger interaction between the Ser605del POLD1 variant and TRF1. Experiments on MDPL fibroblasts confirmed a stronger POLD1–TRF1 binding and revealed dysregulation of PARP1, involved in telomere maintenance. Following X-ray irradiation, aimed at exacerbating the cellular phenotype, we observed a decreasing trend in these markers, which reached statistical significance particularly in one older patient. Conclusions We identified a novel short linear motif (FSLYP) in the Ser605del POLD1 protein that mediates abnormal interaction with TRF1, revealing a structural and functional link between POLD1 and telomere biology, contributing to premature aging phenotypes. This work provides new insights into MDPL pathogenesis and lays the foundation for future research into aging-related therapies.

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae , displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.

Background Paediatric-type diffuse High-Grade Gliomas (PDHGG) are highly heterogeneous tumours which include distinct cell sub-populations co-existing within the same tumour mass. We have previously shown that primary patient-derived and optical barcoded single-cell-derived clones function as interconnected networks. Here, we investigated the role of exosomes as a route for inter-clonal communication mediating PDHGG migration and invasion. Results A comprehensive characterisation of seven optical barcoded single-cell-derived clones obtained from two patient-derived cell lines was performed. These analyses highlighted extensive intra-tumour heterogeneity in terms of genetic and transcriptional profiles between clones as well as marked phenotypic differences including distinctive motility patterns. Live single-cell tracking analysis of 3D migration and invasion assays showed that the single-cell-derived clones display a higher speed and longer travelled distance when in co-culture compared to mono-culture conditions. To determine the role of exosomes in PDHGG inter-clonal cross-talks, we isolated exosomes released by different clones and characterised them in terms of marker expression, size and concentration. We demonstrated that exosomes are actively internalized by the cells and that the inhibition of their biogenesis, using the phospholipase inhibitor GW4689, significantly reduced the cell motility in mono-culture and more prominently when the cells from the clones were in co-culture. Analysis of the exosomal miRNAs, performed with a miRNome PCR panel, identified clone-specific miRNAs and a set of miRNA target genes involved in the regulation of cell motility/invasion/migration. These genes were found differentially expressed in co-culture versus mono-culture conditions and their expression levels were significantly modulated upon inhibition of exosome biogenesis. Conclusions In conclusion, our study highlights for the first time a key role for exosomes in the inter-clonal communication in PDHGG and suggests that interfering with the exosome biogenesis pathway may be a valuable strategy to inhibit cell motility and dissemination for these specific diseases.

Cardiovascular diseases (CVDs) represent a major concern for global health, whose mechanistic understanding is complicated by a complex interplay between genetic predisposition and environmental factors. Specifically, heart failure (HF), encompassing dilated cardiomyopathy (DC), ischemic cardiomyopathy (ICM), and hypertrophic cardiomyopathy (HCM), is a topic of substantial interest in basic and clinical research. Here, we used a Partial Correlation Coefficient-based algorithm (PCC) within the context of a meta-analysis framework to construct a Gene Regulatory Network (GRN) that identifies key regulators whose activity is perturbed in Heart Failure. By integrating data from multiple independent studies, our approach unveiled crucial regulatory associations between transcription factors (TFs) and structural genes, emphasizing their pivotal roles in regulating metabolic pathways, such as fatty acid metabolism, oxidative stress response, epithelial-to-mesenchymal transition, and coagulation. In addition to known associations, our analysis also identified novel regulators, including the identification of TFs FPM315 and OVOL2, which are implicated in dilated cardiomyopathies, and TEAD1 and TEAD2 in both dilated and ischemic cardiomyopathies. Moreover, we uncovered alterations in adipogenesis and oxidative phosphorylation pathways in hypertrophic cardiomyopathy and discovered a role for IL2 STAT5 signaling in heart failure. Our findings underscore the importance of TF activity in the initiation and progression of cardiac disease, highlighting their potential as pharmacological targets.

Recent advances in pharmacogenomics have generated a wealth of data of different types whose analysis have helped in the identification of signatures of different cellular sensitivity/resistance responses to hundreds of chemical compounds. Among the different data types, gene expression has proven to be the more successful for the inference of drug response in cancer cell lines. Although effective, the whole transcriptome can introduce noise in the predictive models, since specific mechanisms are required for different drugs and these realistically involve only part of the proteins encoded in the genome. We analyzed the pharmacogenomics data of 961 cell lines tested with 265 anti-cancer drugs and developed different machine learning approaches for dissecting the genome systematically and predict drug responses using both drug-unspecific and drug-specific genes. These methodologies reach better response predictions for the vast majority of the screened drugs using tens to few hundreds genes specific to each drug instead of the whole genome, thus allowing a better understanding and interpretation of drug-specific response mechanisms which are not necessarily restricted to the drug known targets.

Can language be a valuable predictor of genetic diversity even at the level of extremely circumscribed areas of linguistic diversity? We report on the analysis of mtDNA and NRY variation extracted from the whole-genome sequencing of 27 natives of Grecìa Salentina, a geographic area in southern Italy home to a historic Greek-speaking community. With respect to mtDNA, we found similarities with samples from Central Italy and Eastern Balkan, mainly because of the high haplogroups N, K and J1 frequencies. Detailed phylogeographic analyses of these haplogroups reveal instances of Grecìa Salentina-specific lineages. With respect to the NRY, we find similarities with other samples from southern Italy, Anatolia and the Middle East, because of the overwhelming frequency of haplogroup J2a. The new J2a lineages, many of which are specific to Grecìa Salentina, greatly expand the phylogeny of the haplogroup. Haplogroup R1a is also overrepresented, with a new lineage belonging to the GML6 subclade, which is common in the Western Balkans. All the above haplogroups were long recognized as markers of post-Neolithic East-to-West movements through the Balkan Peninsula by land or off its coasts by sea. We conclude that the peculiar component detected in the Grecìa Salentina gene pool is the result of past immigration. Specifically, there was a demic contribution of both sexes, which foreshadows the build-up of an entire community, and subsequent dilution in the surrounding gene pool by admixture occurred only to a limited extent. These results add a genomic dimension to our knowledge of the identity of the Greek-speaking community settled in Grecìa Salentina. To date, the peculiarity of the Grecìa Salentina population was only its linguistic identity, but we now show that it is also supported by a genetic component. The more general hypothesis of a connection between the demic and linguistic structure of the area can now be tested by comparing the genetics of Grecìa Salentina to those of other linguistic enclaves of Balkan origin in southern Italy.

Abstract Transcription factors (TFs) are key regulators of cellular gene expression programs in health and disease. Here we set out to integrate genomic, transcriptomic, and phosphoproteomic data to characterize TF activity in lung adenocarcinoma patients. Using expression data from patient samples and genomic information on TF binding to super-enhancers, starting from a list of 1667 human TFs we calculated a patient-specific activity score and identified 34 with perturbed activity in the cancer samples, as evidenced by the expression of their direct targets. We then leveraged phosphoproteomic data on the same samples to identify phosphorylation events that modulate TF activity. This novel data integration approach to TF characterization led to the identification of ERG as a key regulator in lung adenocarcinoma whose activity strongly correlates with patient survival.

Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.

Glioblastoma is a severe brain tumor characterized by an extremely poor survival rate of patients. Glioblastoma cancer cells escape to standard therapeutic protocols consisting of a combination of ionizing radiation and temozolomide alkylating drugs that trigger DNA damage by rewiring of signaling pathways. In recent years, the up-regulation of factors that counteract ferroptosis has been highlighted as a major driver of cancer resistance to ionizing radiation, although the molecular connection between the activation of oncogenic signaling and the modulation of ferroptosis has not been clarified yet. Here, we provide the first evidence for a molecular connection between the constitutive activation of tyrosine kinases and resistance to ferroptosis. Src tyrosine kinase, a central hub on which deregulated receptor tyrosine kinase signaling converge in cancer, leads to the stabilization and activation of NRF2 pathway, thus promoting resistance to ionizing radiation-induced ferroptosis. These data suggest that the up-regulation of the Src–NRF2 axis may represent a vulnerability for combined strategies that, by targeting ferroptosis resistance, enhance radiation sensitivity in glioblastoma.