Biology subjects

van Vugt, M.

Publications and source records attributed to van Vugt, M..

13 recordsLinked to original sources

bioRxiv2025

Increased activity of PRMT5-MEP50 complex improves survival of chromosomally unstable cancer cells by increasing tolerance to protein aggregation and proteotoxicity

Most cancers display chromosomal instability (CIN), a condition that leads to increased rates of chromosome missegregation and thus yields aneuploidy. CIN and aneuploidy are detrimental to healthy cells and therefore, aneuploid cells rely on aneuploidy-tolerating mechanisms to adopt a malignant fate. We previously found PRMT5 to be frequently amplified in a mouse model for aneuploid T cell lymphoblastic lymphoma. In this study, we investigated a possible role of PRMT5 as an aneuploidy tolerating gene. We report that PRMT5 is prone to aggregation when expressed at supra-stoichiometric levels compared to its obligate partner protein MEP50 (methylosome protein 50, WDR77). Intriguingly, we also find that protein aggregation, induced by CIN, is mitigated by jointly increased expression of PRMT5 and MEP50. Accordingly, concomitant PRMT5:MEP50 expression renders cancer cells less sensitive to proteasome inhibitors and CIN while inhibition sensitizes cells to CIN. Our findings provide a possible explanation for why PRMT5 and MEP50 display increased expression, particularly in aneuploid cancers and might reveal a targetable vulnerability of aneuploid cancer.

cancer biology↗

bioRxiv2025

CIP2A is required for mitotic recruitment of the SLX1/XPF/MUS81 tri-nuclease complex to replication stress-induced DNA lesions to maintain genome integrity

Perturbed DNA replication can lead to incompletely replicated DNA when cells enter mitosis and can interfere with chromosome segregation. Cells therefore require mechanisms to resolve these lesions during mitosis. The CIP2A-TOPBP1 complex is described to function as a molecular tether that connects fragmented DNA molecules. However, whether CIP2A also functions in processing of incompletely replicated DNA remained unclear. We show that CIP2A-TOPBP1 forms large filamentous structures at sites of incomplete DNA replication during mitosis, which recruit the SMX tri-nuclease complex members SLX4, MUS81 and ERCC1/XPF. These structures form in proximity to sites of mitotic DNA synthesis, although CIP2A is not required for mitotic DNA synthesis. In addition to its globular and coiled-coil domain, the unstructured C-terminal domain of CIP2A is essential for CIP2A-TOPBP1 filamentous structure formation and recruitment of the SMX complex. BRCA1-/- and BRCA2-/- cells have increased mitotic DNA lesions that recruit CIP2A and SLX4. We show that the C-terminal part of CIP2A is required for survival of BRCA2-/- cells. Moreover, SLX4 is crucial for genome stability in BRCA2-/- cells. Combined, we demonstrate that CIP2A-TOPBP1 recruits the SMX complex during mitosis, which is required to resolve mitotic DNA lesions, allows faithful chromosome segregation and maintain viability of BRCA2-/- cells.

cell biology↗

bioRxiv2025

WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response

The WEE1 kinase negatively regulates CDK1/2 to control DNA replication and mitotic entry. Genetic factors that determine sensitivity to WEE1 inhibitors (WEE1i) are largely unknown. A genome-wide insertional mutagenesis screen revealed that mutation of EIF2A, a translation regulator, sensitized to WEE1i. Mechanistically, WEE1i treatment triggers a translational shut-down, which is lethal in combination with the reduced translation of EIF2AKO cells. A genome-wide CRISPR-Cas9 screen revealed that inactivation of integrated stress response (ISR) kinases GCN1/2 rescued WEE1i-mediated cytotoxicity. WEE1i induced GCN2 activation, ATF4 upregulation, and altered ribosome dynamics. Loss of the collided ribosome sensor ZNF598 conversely increased sensitivity to WEE1i. Notably, the ISR was not required for WEE1i to induce DNA damage, premature mitotic entry or sensitization to DNA-damaging chemotherapeutics. ISR activation was independent of CDK1/2 activation. Importantly, WEE1i-mediated ISR activation was independent of WEE1 presence, pointing at off-target effects, which are shared by multiple chemically distinct WEE1i. This response was also observed in peripheral blood mononuclear cells. Importantly, low-dose WEE1 inhibition did not induce ISR activation, while it still synergized with PKMYT1 inhibition. Taken together, WEE1i triggers toxic ISR activation and translational shutdown, which can be prevented by low-dose or combination treatments, while retaining the cell cycle checkpoint-perturbing effects.

cancer biology↗

bioRxiv2024

Transfer of IgG from Long COVID patients induces symptomology in mice

SARS-CoV-2 infections worldwide led to a surge in cases of Long COVID, a post-infectious syndrome. It has been hypothesized that autoantibodies play a crucial role in the development of Long COVID and other syndromes, such as fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, we tested this hypothesis by passively transferring total IgG from Long COVID patients to mice. Using Glial Fibrillary Acidic Protein (GFAP) and type-I interferon expression, we stratified patients into three Long COVID subgroups, each with unique plasma proteome signatures. Remarkably, IgG transfer from the two subgroups, which are characterized by higher plasma levels of neuronal proteins and leukocyte activation markers, induced pronounced and persistent sensory hypersensitivity with distinct kinetics. Conversely, IgG transfer from the third subgroup, which are characterized by enriched skeletal and cardiac muscle proteome profiles, reduced locomotor activity in mice without affecting their motor coordination. These findings demonstrate that transfer of IgG from Long COVID patients to mice replicates disease symptoms, underscoring IgGs causative role in Long COVID pathogenesis. This work proposes a murine model that mirrors Long COVIDs pathophysiological mechanisms, which may be used as a tool for screening and developing targeted therapeutics.

immunology↗

bioRxiv2024

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation.

Radiotherapy is a mainstay in cancer treatment, aiming to maximize DNA damage in tumors while minimizing harm to surrounding healthy tissues. However, the collateral damage to normal tissues, especially stem/progenitor cells essential for tissue regeneration and organ function, remains a significant challenge. Here, we investigate the molecular responses to photon and proton irradiation, two key modalities in head and neck cancer treatment, using organoids. Multiomics analysis reveals a stronger double-stranded RNA (dsRNA)-induced type I interferon (IFN-I) response following proton irradiation, driven by loss of heterochromatin regulators and derepression of transposable elements (TEs). This response, mediated by the cytoplasmic sensor RIG-I, enhances the inflammatory signaling initiated by the canonical dsDNA sensors cGAS and ZBP1. Genetic and pharmacological modulation of IFN-I signaling in vitro and in vivo demonstrates its critical role in enhancing stem/progenitor cell activity post-irradiation. Our findings reveal a pro-regenerative role of TE derepression-mediated IFN-I response suggesting this pathway as a promising therapeutic target to mitigate radiation-induced side effects. TeaserTransposable element-mediated type I interferon signaling enhances stem/progenitor cell activity after irradiation.

cell biology↗

bioRxiv2022

The FIGNL1-interacting protein C1orf112 is synthetic lethal with PICH and mediates RAD51 retention on chromatin.

Joint DNA molecules are natural by-products of DNA replication and repair. Persistent joint molecules give rise to ultrafine DNA bridges (UFBs) in mitosis, which compromise sister chromatid separation. The DNA translocase PICH (ERCC6L) plays a central role in UFB resolution. A genome-wide loss-of-function screen was performed to identify the genetic contexts in which cells become dependent on PICH. In addition to genes involved in DNA condensation, centromere stability and DNA damage repair, we identified the uncharacterized protein C1orf112. We find that C1orf112 interacts with and stabilizes the AAA+ ATPase FIGNL1. Inactivation of either C1orf112 or FIGNL1 resulted in UFB formation, prolonged retention of RAD51 on chromatin, impaired replication fork dynamics, and consequently impaired genome maintenance. Combined, our data reveal that inactivation of C1orf112 and FIGNL1 dysregulates RAD51 dynamics at replication forks, resulting in DNA replication defects, and a dependency on PICH to preserve cell viability.

cancer biology↗

bioRxiv2021

Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo

Chromosomal instability is a hallmark of cancer, but also an instigator of aneuploidy-induced stress, reducing cellular fitness. To better understand how cells with CIN adjust to aneuploidy and adopt a malignant fate in vivo, we performed a genome-wide mutagenesis screen in mice. We find that specifically aneuploid tumors inactivate Stat1 signaling in combination with increased Myc activity. By contrast, loss of p53 is common, but not enriched in CIN tumors. Validation in another tissue type confirmed that CIN promotes immune cell infiltration, which is alleviated by Stat1 loss combined with Myc activation, but not with p53 inactivation, or Myc activation alone. Importantly, we find that this mechanism is preserved in human aneuploid cancers. We conclude that aneuploid cancers inactivate Stat1 signaling to circumvent immune surveillance.

cancer biology↗

bioRxiv2021

Thalamic bursts modulate cortical synchrony locally to switch between states of global functional connectivity in a cognitive task

Performing a cognitive task requires going through a sequence of functionally diverse stages. Although it is typically assumed that these stages are characterized by distinct states of cortical synchrony that are triggered by sub-cortical events, little reported evidence supports this hypothesis. To test this hypothesis, we first identified cognitive stages in single-trial MEG data of an associative recognition task, showing with a novel method that each stage begins with local modulations of synchrony followed by a state of directed functional connectivity. Second, we developed the first whole-brain model that can simulate cortical synchrony throughout a task. The model suggests that the observed synchrony is caused by thalamocortical bursts at the onset of each stage, targeted at cortical synapses and interacting with the structural anatomical connectivity. These findings confirm that cognitive stages are defined by distinct states of cortical synchrony and explains the network-level mechanisms necessary for reaching stage-dependent synchrony states. Author summaryA novel machine-learning method was applied to unveil the dynamics of local and cortex-wide neural coordination underlying the fundamental cognitive processes involved in a memory task. To explain how neural activity - and ultimately behavior - was coordinated throughout the task, we developed a whole-brain model that incorporates cognitive mechanisms, anatomy, and neural biophysics. Similar models are used with resting state data, however, simulating a cognitive task remained elusive. The model showed that sub-cortical pulses at the onset of cognitive processes - as hypothesized by cognitive and neurophysiological theories - were sufficient to switch between the states of neural coordination observed. These findings have implications to understand goal-directed cognitive processing and the mechanisms to reach states of neural coordination.

neuroscience↗

bioRxiv2021

A synthetic lethal screen identifies HDAC4 as a potential target in MELK overexpressing cancers

Maternal embryonic leucine zipper kinase (MELK) is frequently overexpressed in cancer, but the role of MELK in cancer is still poorly understood. MELK was shown to have roles in many cancer-associated processes including tumor growth, chemotherapy resistance, and tumor recurrence. To determine whether the frequent overexpression of MELK can be exploited in therapy, we performed a high-throughput screen using a library of Saccharomyces cerevisiae mutants to identify genes whose functions become essential when MELK is overexpressed. We identified two such genes: LAG2 and HDA3. LAG2 encodes an inhibitor of the SCF ubiquitin-ligase complex, while HDA3 encodes a subunit of the HDA1 histone deacetylase complex. We find that one of these synthetic lethal interactions is conserved in mammalian cells, as inhibition of a human homolog of HDA3 (HDAC4) is synthetically toxic in MELK overexpression cells. Altogether, our work might provide a new angle of how to exploit MELK overexpression in cancers and might thus lead to novel intervention strategies.

genetics↗

bioRxiv2021

An mRNA expression-based signature for oncogene-induced replication-stress

BackgroundOncogene-induced replication stress characterizes many aggressive cancers, including triple-negative breast cancer (TNBC). Several drugs are being developed that target replication stress, although it is unclear how tumors with high levels of replication stress can be identified. We aimed to develop a gene expression signature of oncogene-induced replication stress. MethodsTNBC and non-transformed RPE1-TP53wt and RPE1-TP53mut cell lines were engineered to overexpress the oncogenes CDC25A, CCNE1 or MYC. DNA fiber analysis was used to measure replication kinetics. Analysis of RNA sequencing data of cell lines and patient-derived tumor samples (TCGA n=10,592) was used to identify differential gene expression. Immunohistochemical validation was conducted on breast cancer samples (n=330). ResultsRNA sequencing revealed 52 commonly upregulated genes after induction of CDC25A, CCNE1 or MYC in our cell line panel. Integration with gene expression data of TGCA samples with amplification of replication stress-inducing oncogenes (CDC25A, CCNE1, MYC, CCND1, MYB, MOS, KRAS, ERBB2, and E2F1), yielded a six-gene signature of oncogene-induced replication stress (NAT10, DDX27, ZNF48, C8ORF33, MOCS3, and MPP6). Expression of NAT10 in breast cancer samples was correlated with phospho-RPA (R=0.451, p=1.82x10-20) and {gamma}H2AX (R=0.304, p=2.95x10-9). Applying the oncogene-induced replication stress signature to patient samples (TCGA n=8,862 and GEO n=13,912) defined the replication stress landscape across 27 tumor subtypes, and identified diffuse large B cell lymphoma, ovarian cancer, TNBC and colorectal carcinoma as cancer subtypes with high levels of oncogene-induced replication stress. ConclusionWe developed a gene expression signature of oncogene-induced replication stress, which may facilitate patient selection for agents that target replication stress.

cancer biology↗

bioRxiv2021

Modulations of local synchrony over time lead to resting-state functional connectivity in a parsimonious large-scale brain model

Biophysical models of large-scale brain activity are a fundamental tool for understanding the mechanisms underlying the patterns observed with neuroimaging. These models combine a macroscopic description of the within- and between-ensemble dynamics of neurons within a single architecture. A challenge for these models is accounting for modulations of within-ensemble synchrony over time. Such modulations in local synchrony are fundamental for modeling behavioral tasks and resting-state activity. Another challenge comes from the difficulty in parametrizing large scale brain models which hinders researching principles related with between-ensembles differences. Here we derive a parsimonious large scale brain model that can describe fluctuations of local synchrony. Crucially, we do not reduce within-ensemble dynamics to macroscopic variables first, instead we consider within and between-ensemble interactions similarly while preserving their physiological differences. The dynamics of within-ensemble synchrony can be tuned with a parameter which manipulates local connectivity strength. We simulated resting-state static and time-resolved functional connectivity of alpha band envelopes in models with identical and dissimilar local connectivities. We show that functional connectivity emerges when there are high fluctuations of local and global synchrony simultaneously (i.e. metastable dynamics). We also show that for most ensembles, leaning towards local asynchrony or synchrony correlates with the functional connectivity with other ensembles, with the exception of some regions belonging to the default-mode network. Author summaryHere we present and evaluate a parsimonious model of large-scale brain activity. The model represents the brain as a network-of-networks structure. The sub-networks describe the neural activity within a brain region, and the global network encodes interactions between brain regions. Unlike other models, it capture progressive changes of local synchrony and local dynamics can be tuned with one parameter. Therefore the model could be used not only to model resting-state, but also behavioural tasks. Furthermore, we describe a simple framework that can deal with the arduous task of identifying global and local parameters.

neuroscience↗

bioRxiv2021

Identifying Plasmodium falciparum transmission patterns through parasite prevalence and entomological inoculation rate

Monitoring malaria transmission is a critical component of efforts to achieve targets for elimination and eradication. Two commonly monitored metrics of transmission intensity are parasite prevalence (PR) and the entomological inoculation rate (EIR). Using geostatistical methods, we investigate the relationship between Plasmodium falciparum PR and EIR using data collected over 38 months in a rural area of Malawi. Our results indicate that hotspots identified through the EIR and PR partly overlapped during high transmission seasons but not during low transmission seasons. The estimated relationship showed a one-month delayed effect of EIR on PR such that at low transmission levels increases in EIR are associated with rapid rise in PR, but at high transmission levels, decreases in EIR do not translate into notable reductions in PR. Our study emphasises the need for integrated malaria control strategies that combines vector and human host managements monitored by both entomological and parasitaemia indices.

physiology↗

bioRxiv2019

Cyclin E expression is associated with high levels of replication stress in triple-negative breast cancer.

Replication stress entails the improper progression of DNA replication. In cancer cells, including breast cancer cells, an important cause of replication stress is oncogene activation. Importantly, tumors with high levels of replication stress may have different clinical behavior, and high levels of replication stress appear to be a vulnerability of cancer cells, which may be therapeutically targeted by novel molecularly targeted agents. Unfortunately, data on replication stress is largely based on experimental models. Further investigation of replication stress in clinical samples is required to optimally implement novel therapeutics. To uncover the relation between oncogene expression, replication stress and clinical features of breast cancer subtypes, we immunohistochemically analyzed the expression of a panel of oncogenes (Cdc25a, Cyclin E and c-Myc) and markers of replication stress (phospho-Ser33-RPA32 and {gamma}-H2AX) in treatment-naive breast tumor tissues (n=384). Triple-negative breast cancers (TNBCs) exhibited the highest levels of phospho-Ser33-RPA32 (P<0.001 for all tests) and {gamma}-H2AX (P<0.05 for all tests). Moreover, expression levels of Cyclin E (P<0.001 for all tests) and c-Myc (P<0.001 for all tests) were highest in TNBCs. Expression of Cyclin E positively correlated with phospho-RPA32 (Spearman correlation r=0.37, P<0.001) and {gamma}-H2AX (Spearman correlation r=0.63, P<0.001). Combined, these data indicate that replication stress is predominantly observed in TNBCs, and is associated with expression levels of Cyclin E. These results indicate that Cyclin E overexpression may be used as a biomarker for patient selection in the clinical evaluation of drugs that target the DNA replication stress response.

cancer biology↗