Biology subjects

Fischer, M.

Publications and source records attributed to Fischer, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

An AI-based segmentation and analysis pipeline for high-field MR monitoring of cerebral organoids

BackgroundCerebral organoids simulate the structure and function of the developing human brain in vitro, offering a large potential for personalized therapeutic strategies. The enormous growth of this research area over the past decade with its capability for clinical translation makes a non-invasive, automated analysis pipeline of organoids highly desirable. PurposeThis work presents the first application of magnetic resonance imaging (MRI) for the non-invasive quantification and quality assessment of cerebral organoids using an automated analysis tool. Three specific objectives are addressed, namely organoid segmentation to investigate organoid development over time, global cysticity classification, and local cyst segmentation. MethodsNine wildtype cerebral organoids were imaged over nine weeks using high-field 9.4T MRI including a 3D T2*-w and 2D diffusion tensor imaging (DTI) sequence. This dataset was used to train a deep learning-based 3D U-Net for organoid and local cyst segmentation. For global cysticity classification, we developed a new metric, compactness, to separate low- and high-quality organoids. ResultsThe 3D U-Net achieved a Dice score of 0.92{+/-}0.06 (mean {+/-} SD) for organoid segmentation in the T2*-w sequence. For global cysticity classification, compactness separated low- and high-quality organoids with high accuracy (ROC AUC 0.98). DTI showed that low-quality organoids have a significantly higher diffusion than high-quality organoids (p < .001). For local cyst segmentation in T2*-w, the 3D U-Net achieved a Dice score of 0.63{+/-}0.15 (mean {+/-} SD). ConclusionWe present a novel non-invasive approach to monitor and analyze cerebral organoids over time using high-field MRI and state-of-the-art tools for automated image analysis, offering a comparative pipeline for personalized medicine. We show that organoid growth can be monitored reliably over time and low- and high-quality organoids can be separated with high accuracy. Local cyst segmentation is feasible but could be further improved in the future.

developmental biology↗

bioRxiv2023

Functional synapses between small cell lung cancer and glutamatergic neurons

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, clinical recurrence and high rate of mortality. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified a strong and consistent signal for neuronal, synaptic, and glutamatergic signaling gene sets in murine and human SCLC. We show that SCLC cells have the ability to develop intimate contacts with neuronal glutamatergic terminals in vitro, in autochthonous primary lung tumors and in brain-engrafted tumors. These contacts can develop into bona fide synapses, allowing SCLC cells to receive glutamatergic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we show that SCLC cells derive a robust proliferation advantage when co-cultured with neurons. Moreover, the repression of glutamate release and the stimulation of the inhibitory glutamate receptor GRM8 displayed therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells appear to hijack glutamatergic signaling to sustain tumor growth, thereby exposing a novel entry route for therapeutic intervention.

cancer biology↗

bioRxiv2023

Canary in the Forest? Tree mortality and canopy dieback of western redcedar linked to drier and warmer summer conditions

Tree mortality and partial canopy dieback are increasing in many forest ecosystems from unfavorable climate conditions. Examining how tree growth and mortality are affected by climate variability can help identify proximate causes of tree mortality and canopy dieback. We investigated anomalously high mortality rates and partial canopy dieback of western redcedar (Thuja plicata, WRC), a culturally, ecologically, and economically important species in the Pacific Northwest (USA), using tree-ring methods. We sampled trees in three tree status groups--no canopy dieback, partial canopy dieback, and trees that died (0-30 years ago)--from 11 sites in coastal (maritime climate) and interior (continental climate) populations of WRC trees. In our study, WRC tree mortality was portended by on average 4-5 years of declining radial growth. Warmer and drier climate conditions in May and June that extend the annual July-September dry season reduced radial growth in 9 of 11 sites (1975-2020). Defining drought events as warm, dry May-June climate, we found that WRC trees recovered radial growth to pre-drought rates within three years when post-drought climate conditions were average or cooler and wetter than average. However, radial growth recovery from drought was slower or absent when conditions were warmer and drier during the post-drought recovery period, which appeared to lead to the widespread mortality event across coastal populations. Annually resolved tree mortality in coastal populations predominately occurred in 2017-2018 (80% of sampled trees) and coincided with exceedingly hot temperatures and the longest regionally dry period for May to September (1970-2020). In interior populations, tree mortality was associated with warmer, drier conditions from August to September. Our findings forewarn that a warming climate and more frequent and severe seasonal droughts will likely increase the vulnerability of WRC to canopy dieback and mortality and possibly other drought-sensitive trees in one of the worlds largest carbon sinks.

ecology↗

bioRxiv2022

Tail wags the dog is unsupported by biomechanical Modeling of Canidae Tails Use during Terrestrial Motion

Dogs and other members of Canidae utilize their tails for different purposes, including agile movements, such as running and jumping. In this study, we utilized motion capture biomechanical data of a border collie executing an agile rotational jump maneuver. This data created a 17-segment biomechanical model of the border collies (Canis familiaris) limb movement during agile jumps. This model was verified by comparing it to the biomechanical movement and fitting the dogs agile task with an RMSE less than 2.5%. Using this joint model, we held specific segments constant to view their inertial impact on the dog during the aerial phase of jumping. Results suggest that the tail, hind limbs, and fore limb provides little to no inertial advantage during these rotational jump maneuvers. The tail of dogs likely does have a minimal impact on inertia, the opposite of animals like the gecko. This work could alleviate unknown biomechanical use of the tails to understand the behavioral biomechanics of lesser-known species in their ability to use their tail for rapid and taxing behaviors, including sprinting or climbing.

biophysics↗

bioRxiv2022

Loss of species richness with land use intensity is explained by a reduction in niche differences.

Increases in land use intensity (LUI) reduce species richness. However, we have a poor understanding of how underlying coexistence mechanisms are altered by land use and whether diversity loss occurs due to changes in plant-plant interactions (competition and facilitation) or in species intrinsic growth rates. We expect that LUI could reduce stabilizing niche differences and the indirect interactions that promote coexistence (e.g., intransitivity), while increasing competitive inequalities between species. To test the importance of these different processes, we use 8-yr time series from 150 grasslands differing in LUI to evaluate the role of direct and indirect interactions in promoting coexistence between 50 plant species. We show that LUI reduces the number of coexisting species mostly by causing a non-linear reduction in niche differences, rather than by enhancing competitive inequalities. However, surprisingly, niche differences remained important in stabilizing coexistence between those species remaining at high LUI. Indirect interactions were generally less important than direct ones, and played a moderate role in promoting coexistence in smaller assemblages of species at intermediate LUI. Our models could accurately reproduce the decline in diversity seen with LUI, indicating that our time series approach captures the important interactions between species. By analyzing land use effects through recent advances in structural stability applied to community ecology we provide a more mechanistic understanding of its effects. Our results highlight the importance of identifying the niche differences that are lost with increasing LUI, to better predict and manage effects of land use on biodiversity. Significant statementHuman land use is a major threat to grassland biodiversity. Grasslands with high rates of fertilization, grazing and mowing, contain many fewer plant species. Knowing the underlying causes is necessary for a better management of biodiversity. Here we apply ecological theory to spatiotemporal data on changes in plant abundance in managed grasslands in central Europe. We show that the observed decline in diversity can be explained by how interactions among plant species change with increases in land use intensity. In particular, intensive land use removes the stabilizing effect of self-limiting processes that buffer species against extinction as well as limit competitive dominance. Therefore, actions to promote these stabilizing dynamics among interacting species seem key to restore plant diversity.

ecology↗

bioRxiv2022

m6A modification of TERRA RNA is required for telomere maintenance and is a therapeutic target for ALT positive Neuroblastoma

Telomerase-negative tumors maintain telomere length by alternative lengthening of telomeres (ALT), but the underlying mechanism behind ALT remains poorly understood. A proportion of aggressive neuroblastoma (NB), particularly relapsed tumors, are positive for ALT (ALT+), suggesting that a better dissection of the ALT mechanism could lead to novel therapeutic opportunities. TERRA, a long non-coding RNA (lncRNA) derived from telomere ends, localizes to telomeres in a R-loop-dependent manner and plays a crucial role in telomere maintenance. Here we present evidence that RNA modification at the N6 position of internal adenosine (m6A) in TERRA by the methyltransferase METTL3 is essential for telomere maintenance in ALT+ cells, and the loss of TERRA m6A/METTL3 results in telomere damage. We observed that m6A modification is abundant in R-loop enriched TERRA, and the m6A-mediated recruitment of hnRNPA2B1 to TERRA is critical for R-loop formation. Our findings suggest that m6A drives telomere targeting of TERRA via R-loops, and this m6A-mediated R-loop formation could be a widespread mechanism employed by other chromatin-interacting lncRNAs. Furthermore, treatment of ALT+ NB cells with a METTL3 inhibitor resulted in compromised telomere targeting of TERRA and accumulation of DNA damage at telomeres, indicating that METTL3 inhibition may represent a therapeutic approach for ALT+ NB.

cancer biology↗

bioRxiv2022

Multi-omics analysis identifies RFX7 targets involved in tumor suppression and neuronal processes

Recurrently mutated in lymphoid neoplasms, the transcription factor RFX7 is emerging as a tumor suppressor. Previous reports suggested that RFX7 may also have a role in neurological and metabolic disorders. We recently reported that RFX7 responds to p53 signaling and cellular stress. Furthermore, we found RFX7 target genes to be dysregulated in numerous cancer types also beyond the hematological system. However, our understanding of RFX7s target gene network and its role in health and disease remains limited. Here, we generated RFX7 knock-out cells and employed a multi-omics approach integrating transcriptome, cistrome, and proteome data to obtain a more comprehensive picture of RFX7 targets. We identify novel target genes linked to RFXs tumor suppressor function and underscoring its potential role in neurological disorders. Importantly, our data reveal RFX7 as a mechanistic link that enables the activation of these genes in response to p53 signaling.

genomics↗

bioRxiv2022

African swine fever virus - variants on the rise

African swine fever virus (ASFV), a large and complex DNA-virus circulating between soft ticks and indigenous suids in sub-Saharan Africa, has made its way into swine populations from Europe to Asia. This virus, causing a severe haemorrhagic disease (African swine fever) with very high lethality rates in wild boar and domestic pigs, has demonstrated a remarkably high genetic stability for over 10 years. Consequently, analyses into virus evolution and molecular epidemiology often struggled to provide the genetic basis to trace outbreaks while few resources have been dedicated to genomic surveillance on whole-genome level. During its recent incursion into Germany in 2020, ASFV has unexpectedly diverged into five clearly distinguishable linages with at least ten different variants characterized by high-impact mutations never identified before. Noticeably, all new variants share a frameshift mutation in the 3 end of the DNA polymerase PolX gene O174L, suggesting a causative role as possible mutator gene. Although epidemiological modelling supported the influence of increased mutation rates, it remains unknown how fast virus evolution might progress under these circumstances. Moreover, a tailored Sanger sequencing approach allowed us, for the first time, to trace variants with genomic epidemiology to regional clusters. In conclusion, our findings suggest that this new factor has the potential to dramatically influence the course of the ASFV pandemic with unknown outcome. Therefore, our work highlights the importance of genomic surveillance of ASFV on whole-genome level, the need for high-quality sequences and calls for a closer monitoring of future phenotypic changes of ASFV.

genomics↗

bioRxiv2022

Non-aging despite high mutation rate - genomic insights into the evolution of Hydra

Hydra is a genus of freshwater polyps with remarkable regeneration abilities and a non-senescent phenotype under laboratory conditions. Thus, this animal is particularly interesting for aging research. Here, we gained insights into Hydras recent genetic evolution by genome sequencing of single cells and whole individuals. Despite its extreme longevity, Hydra does not show a lower somatic mutation rate than humans or mice. While we identify biological processes that have evolved under positive selection in animals kept in optimal laboratory conditions for decades, we found no signs of strong negative selection during this tiny evolutionary window. Interestingly, we observe the opposite pattern for the preceding evolution in the wild over a longer time period. Moreover, we found evidence that Hydra evolution in captivity was accompanied and potentially accelerated by loss of heterozygosity. Processes under positive selection in captive animals include pathways associated with Hydras simple nervous system, its nucleic acid metabolic process, cell migration, and hydrolase activity. Genes associated with organ regeneration, regulation of mRNA splicing, histone ubiquitination, and mitochondrial fusion were identified as highly conserved in the wild. Remarkably, several of the processes under strongest selection are closely related to those considered essential for the exapted, i. e. not brought about by natural selection, feature: Hydras non-aging.

evolutionary biology↗

bioRxiv2022

Therapeutic neutralizing monoclonal antibody administration protects against lethal viscerotropic Yellow Fever infection

Few countermeasures to treat Yellow Fever virus (YFV) infection are under development, because vaccines have helped to limit new infections. Unfortunately, vaccine hesitancy, supply deficits, and a paucity of therapeutic options have left individuals at risk. Here, we tested potent YFV-specific neutralizing monoclonal antibodies in rodents and non-human primates. We administered antibodies during acute pathogenic YFV infection and demonstrate that we can prevent severe disease and death. Given the severity of YFV-induced disease, our results show that these antibodies could be effective in saving lives and fill a much-needed void in managing Yellow Fever cases during outbreaks around the world. One Sentence SummaryTherapeutic monoclonal antibodies prevent death from YFV infection.

immunology↗

bioRxiv2022

Selenocysteine metabolism is a targetable vulnerability in MYCN-amplified cancers

Understanding the operational molecular, and metabolic networks that determine the balance between pro- and anti-ferroptotic regulatory pathways could unravel unique vulnerabilities to be exploited for cancer therapy. Here we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis in vitro and in orthotopic neuroblastoma mouse models. Specifically, the exquisite dependency on LRP8-mediated selenocysteine import is caused by the failure of MYCN-amplified cells to efficiently utilize alternative forms of selenium/selenocysteine based uptake necessary for selenoprotein biosynthesis. Increased activity of one of such transporters, SLC7A11, in MYCN-amplified cells leads to cysteine overload, progressive mitochondrial decline and impaired proliferation. These data reveal in LRP8 a targetable, and specific vulnerability of MYCN-amplified neuroblastoma cells and disclose a yet-unaccounted mechanism for selective ferroptosis induction that has the potential to become an important therapeutic entry point for MYCN-amplified neuroblastoma. Statement of significanceGiven the largely unsuccessful repurposing of adult oncology drugs for the treatment of neuroblastoma, our discoveries pave the way for novel ferroptosis based strategies for this entity. Specifically, targeting of LRP8 may offer novel therapeutic and safer opportunities for a number of pediatric malignancies and MYCN driven cancers.

cancer biology↗

bioRxiv2022

Changes of oscillatory and aperiodic neuronal activity in working memory following anaesthesia: a prospective observational study

BackgroundAnaesthesia and surgery can lead to cognitive decline, especially in the elderly. However, to date, the neurophysiological underpinnings of perioperative cognitive decline remain unknown. MethodsWe included male patients, who were 60 years or older scheduled for elective radical prostatectomy under general anaesthesia. We obtained neuropsychological (NP) tests as well as a visual match-to-sample working memory (WM) task with concomitant 62-channel scalp electroencephalography (EEG) before and after surgery. ResultsA total number of 26 patients completed neuropsychological assessments and EEG pre- and postoperatively. Behavioural performance declined in the neuropsychological assessment after anaesthesia (total recall; t-tests: t25 = -3.25, Bonferroni-corrected p = 0.015 d = -0.902), while WM performance showed a dissociation between match and mis-match accuracy (rmANOVA: match*session F1,25 = 3.866, p = 0.060). Distinct EEG signatures tracked behavioural performance: Better performance in the NP assessment was correlated with an increase of non-oscillatory (aperiodic) activity, reflecting increased cortical activity (cluster permutation tests: total recall r = 0.66, p = 0.029, learning slope r = 0.66, p = 0.015), while WM accuracy was tracked by distinct temporally-structured oscillatory theta/alpha (7 - 9 Hz), low beta (14 - 18 Hz) and high beta/gamma (34 - 38 Hz) activity (cluster permutation tests: matches: p < 0.001, mis-matches: p = 0.022). ConclusionsOscillatory and non-oscillatory (aperiodic) activity in perioperative scalp EEG recordings track distinct features of perioperative cognition. Aperiodic activity provides a novel electrophysiological biomarker to identify patients at risk for developing perioperative neurocognitive decline.

neuroscience↗

bioRxiv2021

TargetGeneReg 2.0: a comprehensive web-atlas for p53, p63, and cell cycle-dependent gene regulation

In recent years, our web-atlas at www.TargetGeneReg.org has enabled many researchers to uncover new biological insights and to identify novel regulatory mechanisms that affect p53 and the cell cycle - signaling pathways that are frequently dysregulated in diseases like cancer. Here, we provide a substantial upgrade of the database that comprises an extension to include non-coding genes and the transcription factors {Delta}Np63 and RFX7. TargetGeneReg 2.0 combines gene expression profiling and transcription factor DNA binding data to determine, for each gene, the response to p53, {Delta}Np63, and cell cycle signaling. It can be used to dissect common, cell type, and treatment-specific effects, identify the most promising candidates, and validate findings. We demonstrate the increased power and more intuitive layout of the resource using realistic examples.

bioinformatics↗

bioRxiv2021

Reversible brain edema in experimental cerebral malaria is associated with transcellular blood-brain barrier disruption and delayed microhemorrhages

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as investigations have been hampered by inadequate animal models. In this study, we show that reversible brain swelling in experimental murine cerebral malaria (ECM) can be induced reliably after single vaccination with radiation-attenuated sporozoites as revealed by in vivo high-field (9.4T) magnetic resonance imaging. Our results provide evidence that parenchymal fluid increase and consecutive brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In a cohort of 27 pediatric and adult CM patients (n=4 fatal, n=23 non-fatal) two out of four fatal CM patients (50%) and 8 out of 23 non-fatal CM patients (35%) showed microhemorrhages on MRI at clinical field strength of 1.5T, emphasizing the translational potential of the experimental model. Our data suggest that targeting transcellular BBBD may represent a promising adjunct therapeutic approach in cerebral brain swelling to reduce edema and may ultimately lead to a reduced permanent brain damage and a better longtime neurological outcome. Author summaryBrain swelling, which occurs in diseases such as cerebral malaria, is not necessarily fatal, and may reverse. Even upon reversal of brain swelling, neurological sequelae can still occur. The factors contributing to the reversibility of brain edema are not known, and treatment options remain therefore limited. Identifying the mechanisms leading to such reversibility could inform clinical management aimed at decreasing brain swelling and consecutive brain injury. Here we introduce a reproducible and simple animal model that allows comprehensive in vivo studies of reversible brain swelling in cerebral malaria at the peak of disease and upon recovery. We identify a specific type of blood-brain barrier disruption (BBBD) as a mechanism that occurs in brain swelling. We show that BBBD can reverse, but also highlight remaining brain damage in areas of most severe BBBD. As the ECM model introduced here bares crucial similarities to the CM in humans, our findings open strategies to study new therapeutic avenues and point to compounds that specifically target transcellular BBBD to reduce brain edema, and increase survival rates.

neuroscience↗

bioRxiv2021

Parental environmental effects are common and strong, but unpredictable, in Arabidopsis thaliana

The phenotypes of plants can be influenced by the environmental conditions experienced by their parents. In some cases, such parental effects have been found to be adaptive, which has led to much speculation about their ecological and evolutionary significance. However, there is still much uncertainty about how common and how predictable parental environmental effects really are. We carried out a comprehensive test for parental effects of different environmental stresses in the model plant Arabidopsis thaliana. We subjected plants of three Arabidopsis genotypes to a broad range of biotic or abiotic stresses, or combinations thereof, and compared their offspring phenotypes in a common environment. The majority of environmental stresses (16 out of 24 stress treatments) caused significant parental effects, in particular on plant biomass and reproduction, with positive or negative effects ranging from -35% to +38% changes in offspring fitness. The expression of parental effects was strongly genotype-dependent, with some effects only present in some genotypes but absent, or even in the opposite direction, in others. Parental effects of multiple environmental stresses were often non-additive, and their effects can thus not be predicted from what we know about the effects of individual stresses. Intriguingly, the direction and magnitude of parental effects were unrelated to the direct effects on the parents: some stresses did not affect the parents but caused substantial effects on offspring, while for others the situation was reversed. In summary, parental environmental effects are common and often strong in A. thaliana, but they are genotype-dependent and difficult to predict. SignificanceStress experienced by plants can alter the phenotypes of their offspring. To understand the ecological and evolutionary significance of such parental effects, we must know how common and how predictable they are. In a large experiment with Arabidopsis thaliana, we show that the majority of 24 environmental stresses cause significant, and often strong, positive or negative parental effects. However, we also find that parental effects are genotype-specific and unrelated to the direct effect of individual stresses, and that multiple stresses often act in non-additive ways across generations. Thus, parental effects appear to be common and strong, but difficult to predict. Our findings have important implications for the study of plant responses to environmental change, and the design of stress experiments.

ecology↗

bioRxiv2021

ProteinPrompt: a webserver for predictingprotein-protein interactions

MotivationProtein-protein interactions play an essential role in a great variety of cellular processes and are therefore of significant interest for the design of new therapeutic compounds as well as the identification of side-effects due to unexpected binding. Here, we present ProteinPrompt, a webserver that uses machine-learning algorithms to calculate specific, currently unknown protein-protein interactions. Our tool is designed to quickly and reliably predict contacts based on an input sequence in order to scan large sequence libraries for potential binding partners, with the goal to accelerate and assure the quality of the laborious process of drug target identification. MethodsWe collected and thoroughly filtered a comprehensive database of known contacts from several sources, which is available as download. ProteinPrompt provides two complementary search methods of similar accuracy for comparison and consensus building. The default method is a random forest algorithm that uses the auto-correlations of seven amino acid scales. Alternatively, a graph neural network implementation can be selected. Additionally, a consensus prediction is available. For each query sequence, potential binding partners are identified from a protein sequence database. The proteom of several organisms are available and can be searched for contacts. ResultsTo evaluate the predictive power of the algorithms, we prepared a test dataset that was rigorously filtered for redundancy. No sequence pairs similar to the ones used for training were included in this dataset. With this challenging dataset, the random forest method achieved an accuracy rate of 0.88 and an area under curve of 0.95. The graph neural network achieved an accuracy rate of 0.86 using the same dataset. Since the underlying learning approaches are unrelated, comparing the results of random forest and graph neural networks reduces the likelihood of errors. The consensus reached an accuracy of 0.89. ProteinPrompt is available online at: http://proteinformatics.org/ProteinPrompt The server makes it possible to scan the human proteome for potential binding partners of an input sequence within minutes. For local offline usage, we furthermore created a ProteinPrompt Docker image which allows for batch submission: https://gitlab.hzdr.de/Proteinprompt/ProteinPrompt. In conclusion, we offer a fast, accurate, easy-to-use online service for predicting binding partners from an input sequence.

bioinformatics↗

bioRxiv2021

Biochemical characterization of a human septin octamer

1Septins are part of the cytoskeleton and polymerize into non-polar filaments of heteromeric hexamers or octamers. They belong to the class of P-loop GTPases but the roles of GTP binding and hydrolysis on filament formation and dynamics are not well understood. The basic human septin building block is the septin rod, a hetero-octamer composed of SEPT2, SEPT6, SEPT7, and SEPT9 with a stoichiometry of 2:2:2:2 (2-7-6-9-9-6-7-2). Septin rods polymerize by end-to-end and lateral joining into linear filaments and higher ordered structures such as rings, sheets, and gauzes. We purified a recombinant human septin octamer from E. coli for in vitro experimentation that is able to polymerize into filaments. We could show that the C-terminal region of the central SEPT9 subunit contributes to filament formation and that the human septin rod decreases the rate of in vitro actin polymerization. We provide further first kinetic data on the nucleotide uptake- and exchange properties of human hexameric and octameric septin rods. We could show that nucleotide uptake prior to hydrolysis is a dynamic process and that a bound nucleotide is exchangeable. However, the hydrolyzed {gamma}-phosphate is not released from the native protein complex. We consequently propose that GTP hydrolysis in human septins does not follow the typical mechanism known from other small GTPases.

biochemistry↗

bioRxiv2021

MYCN mediates cysteine addiction and sensitizes to ferroptosis

Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYC induces massive lipid peroxidation upon depletion of cysteine, the rate-limiting amino acid for glutathione biosynthesis and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and irondependent type of cell death. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. MYCN may contribute to spontaneous tumor regression in low-risk neuroblastomas by promoting ferroptosis in cells with epigenetically silenced cystathionine-beta-synthase, the rate-limiting enzyme for transsulfuration. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically.

cancer biology↗