Biology subjects

Subtil, F. T.

Publications and source records attributed to Subtil, F. T..

3 recordsLinked to original sources

bioRxiv2026

MEN1 deficiency establishes a selenite-dependent binary switch in ferroptosis

Replication stress is a hallmark of cancer cells, yet the factors determining tolerance remain poorly understood. Genome-wide CRISPR screens for modifiers of replication-stress responses identified loss of the chromatin scaffold gene MEN1 as a resistance factor. We show that MEN1 deficiency suppresses lipid peroxidation and ferroptotic death, enabling survival following treatment with multiple replication stress-inducing agents. Mechanistically, MEN1 loss reduced H3.3 occupancy at ACSL1 regulatory regions and lowered ACSL1 expression, with ACSL1 loss phenocopying replication stress resistance. MEN1- or ACSL1-deficient cells also exhibited reduced levels of SLC7A11 and glutathione, rendering them hypersensitive to GPX4 inhibition under selenite-limiting conditions. Conversely, selenite supplementation preferentially increased GPX4 abundance and converted these cells to a ferroptosis-resistant state independently of SLC7A11. Thus, MEN1 links chromatin regulation to the ferroptotic control of replication stress responses, while selenite availability determines whether MEN1-deficient cells are vulnerable or resistant.

cell biology↗

bioRxiv2026

Phenotype-first covalent fragment screening identifies a synthetic lethal TYMS inhibitor in ATRX-deficient cells

Chemoproteomic mapping of covalent fragment libraries is expanding the ligandable human proteome with direct evidence of cellular target engagement. However, understanding the functional consequences of specific covalent modifications typically requires extensive downstream biological characterisation. Here we present a phenotype-first approach that integrates covalent fragment screening with chemoproteomics and genetic deconvolution in a disease-relevant context. Using isogenic ATRX wild-type and knockout eHAP iCAS9 cells, we screened a library of around 500 cysteine-reactive fragments for differential cell killing and identified a chloroacetamide fragment, PP12, that selectively impairs the viability of ATRX-deficient cells. By combining competitive click-chemoproteomics with genome-wide CRISPR synthetic lethal datasets, we identified thymidylate synthase (TYMS) as a phenotypically relevant target of PP12. Target validation was supported by crystallography, competition with the active-site inhibitor 5-fluorouracil, and impaired dTMP synthesis in cells. Mechanistically, TYMS inhibition induces replication stress that is selectively cytotoxic to ATRX-deficient cells and is dependent on FAM111A and SLFN11. This work establishes a generalisable workflow linking covalent fragment phenotypes to target deconvolution using chemoproteomics and mechanistic validation.

cell biology↗

bioRxiv2026

The antipsychotic drug clozapine suppresses autoimmunity driving psychosis-like behavior in mice

Antipsychotic drugs are the first-line treatment for psychosis yet their mechanism of action remains poorly understood, largely due to the challenge to faithfully model psychosis preclinically. Here, we focus on the emerging concept that psychosis can be caused by brain autoimmunity and present a novel mouse model of anti-N-methyl-D-aspartate-receptor (anti-NMDAR) encephalitis, a condition that manifests with psychosis and autoanti-bodies against the NMDAR. We devised a new mRNA-based approach to immunize mice against the NMDAR. Immunized mice developed psychosis-like behaviors that were caused by anti-NMDAR autoantibodies leading to phagocytosis of NMDARs by brain microglia. The antipsychotic drug clozapine rescued psychosis-like behaviors and, remarkably, reduced anti-NMDAR autoantibody levels and antibody-mediated phagocytosis of NMDARs. The immunomodulatory effects of clozapine were confirmed in a mouse model of systemic lupus erythematosus. Our results demonstrate that clozapine suppresses autoimmunity driving psychosis-like behaviors, raising the possibility that immunomodulation contributes to antipsychotic drug action. HIGHLIGHTSO_LImRNA immunization against the NMDAR induces psychosis-like behavior in mice C_LIO_LIAnti-NMDAR autoantibodies are sufficient for psychosis-like behavior C_LIO_LIMicroglial phagocytosis of NMDARs mediates psychosis-like behavior induced by anti-NMDAR autoanti-bodies. C_LIO_LIClozapine reduces anti-NMDAR autoantibodies, microglial phagocytosis and psychosis-like behavior, consistent with immunomodulation as a potential mechanism of antipsychotic drug action. C_LI

neuroscience↗