Biology subjects

Kim, Y.

Publications and source records attributed to Kim, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Predictive learning induces Bayesian cognitive maps in the hippocampus

Navigation requires perception: location must be inferred from noisy and ambiguous egocentric sensory inputs, as in visual estimation of distance. However, many classical models of spatial representation implicitly assume that allocentric location is directly observable, thereby neglecting perceptual uncertainty. Here, we compare such a model with a Bayesian ideal observer that explicitly incorporates perceptual inference. We find that the Bayesian observers beliefs over location more accurately reproduce key properties of place cell activity, including place field width, area, and density, within and across environments. Using analytic arguments and numerical simulations, we show that recurrent neural networks trained to predict the next egocentric sensory input learn representations resembling Bayesian beliefs and yield place cell-like activity in both familiar and unfamiliar environments, outperforming autoencoders trained to reproduce the current input. Together, these results suggest that hippocampal circuits may construct Bayesian cognitive maps from experience through predictive perceptual learning.

neuroscience↗

bioRxiv2026

Engineering Carbon Nanotube Quantum Well Defects with Recognition Tripeptides for Optical Detection of Extracellular Vesicles in Plasma

Extracellular vesicles (EVs) carry molecular signatures of their originating cells and have thus emerged as promising biomarkers. However, their clinical utility remains limited due to their low abundance and the modest sensitivity of current EV detection methods in complex biological environments. Here, we present a quantum well defect functionalized carbon nanotube sensor coupled with integrin-recognition RGD tripeptide for EV detection in human plasma. Leveraging the abundance of integrins on EV surfaces, we targeted 5{beta}1, V{beta}1, and V{beta}3 subtypes. The nanosensor exhibited robust hypsochromic shifts in defect emission upon integrin binding, achieving sub-picomolar detection limits for integrin subunits and quantifying EVs at concentrations as low as 104 EVs{middle dot}mL-1 for glioblastoma, ovarian cancer, and fibroblast cell-derived EV types. Molecular dynamics simulation indicated that integrin docking at the RGD-coupled quantum defect can substantially reshape the interfacial environments of the quantum defects, explaining the high sensitivity in EV detection in complex biological media. Finally, transmembrane protein analysis validated the expression of surface integrins across the tested EV types. The modular nanosensor construct can be targeted to detect disease-associated EV subpopulations, advancing EV-based diagnostics.

biochemistry↗

bioRxiv2026

Reproducible and shareable bioinformatics pipelines from natural-language prompts

Large language models (LLMs) are increasingly used to generate bioinformatics pipelines and to carry out analyses from natural-language prompts. However, the resulting analyses are often difficult to reproduce across sessions, owing to the non-deterministic nature of LLM-driven conversations and heterogeneity of local execution environments, and cannot run on remote high-performance computing (HPC) servers or be shared and reused. We present Autopipe, a platform that guides any Model Context Protocol (MCP) - compatible LLM to produce, execute, and publish source-preserved, re-executable containerized pipelines. Autopipe enables users to execute bioinformatics pipelines on any on-premises remote servers - supported by comprehensive setup documentation aimed at researchers without prior server-administration experience - and to visualize results through an extensible web-based viewer. The Autopipe platform comprises four components: a desktop application with an embedded MCP server for pipeline management and remote execution, an online registry for pipeline and plugin discovery, a web-based result viewer, and a CLI tool for customizing viewer plugins. Autopipe turns conversational analysis into re-executable and shareable workflows. Autopipe is freely available at https://autopipe.org/.

bioinformatics↗

bioRxiv2026

Lamin dosage in cardiomyocytes supports nuclear organization and chromatin gating for transcription

The nuclear lamina contains intermediate filaments, called lamins, which function to maintain nuclear integrity and organize the Lamina-Associated chromatin Domains (LADs). Despite near ubiquitous expression, lamins show cell-type-specific functions. In the heart, they support epicardial cell migration, cardiomyocyte nuclear integrity and maturation. How these functions are integrated with different gene expression programs in these cells during heart development is unknown. We show that cardiomyocytes require lamin-A and -B1 for perinatal mouse survival. Importantly, lamin-B1 facilitates timely cardiomyocyte maturation by maintaining LADs and chromosome territories. By examining changes in cardiomyocyte gene expression and 3D genome organization upon lamin-B1 deletion, we show lamin-B1 maintains chromatin neighborhoods, which can in turn support transcription factors that regulate genes involved in cardiomyocyte structural maturation and gradual cessation of cell division. We propose a genomic logic by which the widely expressed lamins collaborate with transcription factors to specifically promote cardiomyocyte maturation and cell cycle exit during development. HighlightsO_LILamin-A/B1 dose-dependently set cardiomyocyte nuclear order and postnatal survival. C_LIO_LILamin-B1 loss disrupts transcription programs for cardiomyocyte maturation. C_LIO_LILamin-B1 shapes chromatin neighborhoods to support cardiomyocyte maturation programs. C_LI

molecular biology↗

bioRxiv2026

Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation

Copper (Cu) is an essential cofactor for mitochondrial cytochrome c oxidase, yet whether it directly regulates mitochondrial metabolism beyond respiration remains unclear. Here we show that mitochondrial Cu, delivered by SLC25A3, is required to maintain the stability of lipoylated TCA cycle proteins. Loss of Slc25a3 or pharmacological Cu depletion selectively destabilized the lipoylated E2 subunits of mitochondrial dehydrogenases and the lipoylation enzymes LIPT1 and LIPT2, an effect not reproduced by acute electron transport chain inhibition. Mechanistically, we find that Cu directly engages the reduced lipoyl moiety using chemical probes and synthetic peptide approaches. Cu depletion impaired PDH and OGDH activity, rewired TCA cycle metabolism, and imposed a dependence on pyruvate carboxylase for anaplerosis. This metabolic defect depleted aspartate, suppressed mTORC1 signaling, and limited proliferation. Conversely, selective delivery of Cu to the mitochondria restored lipoylation, TCA cycle function, and cell growth. Together, these findings identify mitochondrial Cu as a structural regulator of the lipoylation machinery and reveal a direct link between Cu homeostasis and central carbon metabolism.

cell biology↗

bioRxiv2026

Once yearly cell-based therapy for sustained and dose tunable delivery of monoclonal antibodies

Over 200 monoclonal antibodies (mAbs) are approved for clinical use, yet their therapeutic potential is constrained by dependence on repeated injections or infusions that drive non-adherence, limit access in low-resource settings, and generate peak-trough pharmacokinetics linked to adverse effects and reduced efficacy. Here, we developed an immunomodulatory encapsulated cell-based biologics factory that overcomes mAb instability, immunogenicity, and the fibrotic foreign body response that have limited previous approaches, enabling continuous in situ production of therapeutic antibodies from a single administration. Screening chemically modified alginate biomaterials in immunocompetent mice identified a lead immunomodulatory alginate formulation that sustains stable serum titers of the HIV-neutralizing mAb 3BNC117 for one year. Single-cell RNA sequencing revealed that this formulation promotes a local anti-inflammatory, pro-resolving immune niche that attenuates fibrosis. The platforms versatility was demonstrated by production of thirteen diverse mAbs from an allogeneic cell chassis, with sustained in vivo delivery of a subset including ipilimumab, pembrolizumab, adalimumab, and PGT121. Integration into a retrievable macrodevice enabled on-demand therapeutic termination and re-implantation for dose-proportional tuning. In a non-human primates, subcutaneous implantation maintained stable ipilimumab titers for over six months with no detectable toxicity, anti-drug antibodies, or adverse events, and dose-dependent exposure was confirmed across a three-dose escalation. These results demonstrate a clinically translatable platform offering a practical strategy to replace frequent injections with single-administration therapy.

bioengineering↗

bioRxiv2026

Astrocytic ACSBG1 depletion improves lipid-cytokine signaling and attenuates α-Synuclein pathology in a Parkinson's disease mouse model

Astrocytes are key regulators of lipid metabolism, and dysregulated astrocytic lipid processing is implicated in Parkinsons disease (PD) pathogenesis. Our prior genome-wide screens identified ACSBG1, an astrocyte-enriched acyl-CoA synthetase, as a candidate regulator of -synuclein (-Syn) levels. However, how ACSBG1 links lipid reprogramming to inflammatory astrocyte activation and -Syn pathology remains unknown. We compared the transcriptomic, cytokine, and lipid secretomes of TNF- and IL-1 stimulated primary astrocytes from wild-type (WT) and Acsbg1 knockout (KO) mice. In vivo, we crossed Acsbg1 KO mice with a Thy1--Syn PD model to assess behavior, neuroinflammation, synaptic integrity, and -Syn levels. Following cytokine exposure, Acsbg1 KO astrocytes mounted an attenuated inflammatory transcriptional response, secreting significantly fewer inflammatory mediators (e.g., IL-6, RANTES, MIP-3) and less long-chain Sphingosine 20:1 than WT astrocytes. Importantly, exogenous Sphingosine 20:1 or cytokines from WT reactive astrocytes induced neuronal -Syn phosphorylation (pS129). In vivo, Acsbg1 deletion in Thy1--Syn mice reduced astrogliosis, rescued synaptic and behavioral deficits, and decreased total and pS129--Syn. These findings establish ACSBG1 as a key regulator of inflammatory astrocyte signaling that contributes to -Syn phosphorylation via specific cytokine and lipid mediators, identifying ACSBG1 as a novel therapeutic target for modulating astrocyte-neuron communication in PD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/726454v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@150a3e3org.highwire.dtl.DTLVardef@137b5caorg.highwire.dtl.DTLVardef@7fe373org.highwire.dtl.DTLVardef@2d996e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

GLP-1 analogs restore inflammatory, mitochondrial and intercellular signaling networks in the SncaG51D/G51D knock-in mouse model of Parkinson's disease

Parkinsons disease (PD) is a neurodegenerative disorder characterized by a prolonged prodromal stage that culminates in motor deficits. Current PD therapies primarily alleviate symptoms, underscoring the need for disease-modifying strategies. Glucagon-like peptide-1 (GLP-1) analogs showed early promise as candidate disease modifiers, but recent clinical results have been inconsistent, and their mechanism of action remains poorly defined. Here, we employed our SncaG51D/G51D knock-in mouse model to investigate the effects of subcutaneously administered GLP-1 analogs, semaglutide and lixisenatide. Both analogs reversed motor and non-motor deficits and reduced gliosis and detergent-insoluble -synuclein. Bulk and single-nuclei transcriptomics together with CellChat-based intercellular communication analysis revealed that GLP-1 analogs normalize early striatal mitochondrial and inflammatory dysregulation and restore neuregulin (NRG) and neurexin (NRXN) signaling networks to wild-type levels. Treatment was effective when initiated either before or shortly after symptom onset, defining an early therapeutic window for GLP-1 analog therapy in PD.

neuroscience↗

bioRxiv2026

Disordered protein COSA-2 maintains crossover-specific repair compartments to ensure meiotic crossover maturation

Faithful genome inheritance during meiosis relies on crossover repair of double-strand DNA breaks (DSBs) to connect homologous chromosomes and direct their proper segregation. The formation of crossover-specific recombination intermediates and accumulation of pro-crossover factors occurs at an extremely limited subset of DSB sites, necessitating that the subset of recombination sites designated to become crossovers reliably mature into crossovers. Here we identify C. elegans disordered protein COSA-2 as crucial for meiotic crossover maturation. COSA-2 abruptly concentrates at crossover intermediates in late pachytene nuclei, where it colocalizes and associates with other pro-crossover factors. COSA-2 is dispensable for early loading of crossover factors and for crossover designation, but is required for maintenance of pro-crossover factors at crossover-designated sites and for focal enrichment of factors initially distributed throughout the synaptonemal complex. We define a COSA-2 execution point during late pachytene wherein crossover intermediates transition from a vulnerable state (in which they require COSA-2 to avoid being dismantled) to a state where COSA-2 and local crossover-factor enrichment are no longer required to connect homologs. We propose that COSA-2 scaffolds privileged DNA repair compartments that promote crossover-factor accumulation and protect crossover intermediates until completion of repair, thereby ensuring that crossover-designated sites reliably mature into crossovers.

developmental biology↗

bioRxiv2026

Staged heavy-chain filtering enables Fab discovery from combinatorially intractable library spaces

BackgroundCombinatorial fragment antigen-binding (Fab) libraries encode an immense heavy-light chain pairing space, often exceeding 10{superscript 1} possible combinations, which far surpasses the diversity that can be experimentally constructed and screened in display systems. As a result, direct Fab screening samples only a small fraction of the theoretical search space, creating a practical bottleneck for functional binder discovery. ResultsHere, we frame Fab discovery as a staged search problem by decoupling heavy-chain (HC) and light-chain (LC) exploration. We implemented a sequential HC preselection-remating workflow in yeast surface display, in which antigen-reactive HC variants are first enriched and subsequently recombined with a diverse LC repertoire to reconstruct a focused Fab library. In a SARS-CoV-2 spike-targeted campaign, HC and LC libraries of 2.05 x 10 and 2.33 x 10 members corresponded to a theoretical pairing space of approximately 4.8 x 10{superscript 1} combinations. Sequential HC enrichment followed by LC remating allowed recovery of multiple functional Fab clones from a tractable library scale of approximately 10, including clones that shared a common HC scaffold but carried distinct LC partners. A representative recombinant IgG output showed broad but heterogeneous spike/RBD binding, measurable pseudovirus neutralization activity (EC = 11.1 nM), and compatibility with standard early biophysical characterization after full-length IgG reformatting. ConclusionsThese results provide proof of principle that combinatorial Fab discovery can be approached as a staged exploration problem under realistic library-size constraints. By focusing downstream Fab reconstruction on an antigen-compatible HC subspace, sequential HC preselection followed by LC remating offers a practical strategy for exploring otherwise intractable antibody pairing landscapes in eukaryotic display systems.

bioengineering↗

bioRxiv2026

Lamins and lineage-relevant transcription factors coordinate gene expression in lineage development

HighlightsO_LILamin-A and lamin-B1 are essential for midgestational embryogenesis. C_LIO_LILamin-A/B1 are required for proper yolk sac endoderm (YSE) gene regulation. C_LIO_LILamin-A/B1 maintain LADs organization and chromatin interactions in YSE. C_LIO_LILamin-A/B1 and YSE transcription factors support proper YSE gene expression. C_LI Lamins are intermediate filament proteins functioning as ubiquitous structural components of the nuclear lamina that interact with and organize the Lamina-Associated chromatin Domains (LADs). LADs remodel during development and lamins maintain LADs and gene expression profile specific to a given cell type. How ubiquitous lamins achieve cell-type-specific functions during development remains unknown. We show lamin-A and -B1 are required for mouse midgestational embryogenesis and maintain LADs, 3D chromatin interactions, and gene expression in the yolk sac endoderm (YSE). Both lamin-regulated genes and remodeled LADs in YSE cells contain binding motifs of YSE-relevant transcription factors. By analyzing changes in chromatin interactions upon lamin-A and -B1 knockout, we reveal that chromatin neighborhoods maintained by these lamins can influence gene expression orchestrated by YSE-relevant transcription factors. Our findings explain how the ubiquitously expressed lamins can collaborate with lineage-relevant transcription factors to maintain LADs and gene expression programs in specific cell types.

developmental biology↗

bioRxiv2026

Phylogenetic Analysis and Structural Evaluation of Staphylococcus aureus Serine-Aspartate Repeat-Containing Protein D with a Focus on Periprosthetic Joint Infection

Serine-aspartate repeat-containing protein D (SdrD) is a Staphylococcus aureus cell wall-anchored, calcium-binding adhesin member of the MSCRAMM Sdr subfamily that may contribute to bacterial adhesion and virulence. S. aureus is the most common cause of periprosthetic joint infection (PJI). Population-level distribution and sequence diversity of SdrD among clinical PJI isolates have not been systematically characterized, and the SdrD binding mechanism is still not well understood. To address these gaps, sdrD alleles were queried across 156 newly sequenced PJI isolates and compared to publicly available S. aureus genomes, and nucleotide- and protein-level phylogenies of the sdrCDE locus constructed. The SdrD crystal structure from S. aureus JH1 was determined, with solution small-angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, and assessment of conformational changes with calcium depletion. Three dominant sdrD subtypes were defined, associating with USA300, JH1, and TCH60; the JH1 sdrD subtype was predominant among PJI isolates. Structural studies showed that the conformation of individual domains and interdomain organization of the multidomain SdrD have limited flexibility in solution, and that the calcium-binding B domain retains its core fold under conditions of calcium depletion. Together, the findings presented support functional diversification among Sdr family members in mediating host attachment and inform a re-evaluation of the ligand-binding mechanism previously proposed for SdrD. AUTHOR SUMMARYStaphylococcus aureus is the leading cause of infections that develop around joint implants (periprosthetic joint infection, PJI). This bacterium has a large arsenal of surface proteins that allow it to stick to human tissues and implanted devices. This work focused on one such protein, SdrD, which has been linked to implant-associated infections but the structure and diversity of which among patients with PJI had not been well characterized. The genetic sequences of SdrD were analyzed across thousands of bacterial genomes, including those from patients with PJI. Distinct genetic variants of the protein were found, one of which was particularly common with PJI. The three-dimensional structure of SdrD was determined at atomic resolution and solution small-angle X-ray scattering (SAXS) and molecular dynamics used to study how it moves and responds to changes in its environment. Contrary to what was previously described, SdrD was shown to be relatively rigid. These findings change how SdrDs mechanism of action should be considered, potentially informing design strategies to block bacterial attachment before infection takes hold.

biophysics↗

bioRxiv2026

Aerosol delivery-based serial femtosecond crystallography

Serial femtosecond crystallography (SFX) has revolutionised structural biology by enabling direct visualization of conformational dynamics of biomacromolecules at near-physiological temperatures. However, conventional SFX sample delivery at X-ray free-electron laser (XFEL) facilities introduces a significant X-ray scattering background, which may limit the data quality and resolution. Here, we introduce an aerosol delivery-based method that drastically reduces the back-ground scattering by minimising the liquid environment surrounding the nanocrystals. We validate our method by solving the structure of Cydia pomonella granulovirus nanocrystals at 1.9 [A] resolution, achieving orders-of-magnitude lower background scattering compared to a liquid jet-based method. Structural comparison with the liquid jet-based model revealed similar overall structure, suggesting that the native structure is largely preserved despite dehydration during aerosolisation. Our method enables efficient SFX studies, particularly pump-probe time-resolved SFX on protein nanocrystals with enhanced signal-to-noise ratios, as well as high-throughput small molecule SFX (smSFX) applications for pharmaceuticals and functional materials.

biophysics↗

bioRxiv2026

TAR syndrome causal gene RBM8A is critical for embryonic bone development and proper Hedgehog signaling

RNA-Binding Motif Protein 8A (RBM8A) is a core component of the exon junction complex (EJC), which plays a fundamental role in post-transcriptional RNA regulation. Mutations in the RBM8A gene cause thrombocytopenia-absent radius (TAR) syndrome, characterized by reduced platelet number and radial defects. However, how its function contributes to bone development remains poorly understood. We found that RBM8A is highly expressed in human bone marrow-derived mesenchymal stem cells (MSCs) and mouse embryonic limb buds. To further investigate the role of RBM8A in bone development, we generated an Rbm8a conditional knockout mouse (cKO) model in the early limb bud and craniofacial mesenchyme using the Prx1-cre line, which recapitulates key features of TAR syndrome. Rbm8a deficiency in this mouse model resulted in significant defects in limb and craniofacial development, including shorter limb bones across developmental timepoints, delayed ossification, altered cranial morphogenesis, along with impairments in motor function and reduced brain size. To elucidate the molecular basis of these phenotypes, we performed RNA immunoprecipitation sequencing (RIP-seq) in embryonic limb tissue. Our analysis revealed that RBM8A preferentially associates with long, exon-rich transcripts with high isoform complexity. These transcripts are enriched in pathways related to primary cilia, RNA processing, and developmental signaling. Consistent with this, transcriptomic and enrichment analyses identified strong associations with ciliopathy-related and congenital skeletal disease gene sets. At the cellular level, Rbm8a deficiency resulted in altered expression of key chondrogenic and ossification markers in embryonic limb bone tissue, such as reduced SOX9 and increased IHH in the primary ossification center, suggesting impaired progression of endochondral ossification and disrupted Hedgehog pathway activity. Quantitative Reverse Transcription-PCR (qRT-PCR) analysis further validated selective downregulation of Hedgehog pathway targets, including Gli3 and Hhip, while other developmental genes remained unchanged, indicating pathway-specific attenuation. Together, these findings support a model in which Rbm8a regulates structurally complex transcripts that are enriched in ciliary and developmental signaling pathways, and that disruption of this process leads to selective impairment of Hedgehog signaling and skeletal development. These results provide a novel mechanistic link between RNA processing and developmental signaling and offer new insight into how defects in RNA regulation contribute to congenital skeletal abnormalities.

developmental biology↗

bioRxiv2026

Histone H4 acetyl-methyllysine marks accessible chromatin that resists compaction

Certain regulatory DNA regions remain accessible even under conditions of widespread chromatin compaction. These regions are often marked by specific protein factors and histone modifications that help maintain their accessibility. Here, we examine the genomic landscape of acetyl-methyllysine (Kacme), a recently discovered histone post-translational modification. Across multiple systems, Kacme is highly enriched at sites of accessible chromatin, including active promoters, enhancers, silencers, and CTCF-binding sites. We find that Kacme is selectively retained at loci that resist condensation during mitosis, marks XIST and escapee regions on the inactive X chromosome in female cells and demarcates the boundaries of broad heterochromatin domains. Kacme-marked insulator elements block heterochromatin spreading and protect adjacent genes from transcriptional repression, even when H3K27me3 levels are pharmacologically elevated through KDM6A/6B inhibition. Taken together, our findings establish the chromatin features associated with Kacme and support a model in which Kacme helps safeguard chromatin accessibility at loci that resist compaction.

molecular biology↗

bioRxiv2026

FOXP-stabilization of the Il2ra super-enhancer structure augments Treg fitness

Gene expression in regulatory T cells (Tregs) is context-dependent and maintains peripheral immune homeostasis. FOXP3 is lineage defining but not sufficient for Treg function or persistence. To define the cell-intrinsic roles of the FOXP3 paralogs FOXP1 and FOXP4, we generated and studied mice with Treg-specific deletion of Foxp1 and/or Foxp4. FOXP1 and FOXP4 are required to maintain the peripheral Treg pool through enhancing Il2ra transcription, thereby promoting sustained high-level expression of IL-2R and thus of the high-affinity IL-2R{beta}{gamma} complex. Integrating RNA-seq and ATAC-seq with previously published ChIA-PET and publicly available data, we propose a model of Il2ra transcriptional regulation in which in which FOXP1 and FOXP4 anchor chromatin looping of the Il2ra locus in mature Tregs, augment super-enhancer activity, and drive sustained CD25 expression. Our results reveal a unique role of FOXP1, and to a lesser extent FOXP4, in controlling Treg homeostasis. One Sentence SummaryFOXP1 and FOXP4 regulate chromatin architecture at the Il2ra locus, promoting sustained CD25 expression and maintaining the peripheral Treg pool.

immunology↗

bioRxiv2026

Controlled linking of AAV capsids enables coordinated multi-vector delivery

Adeno-associated virus (AAV)-based delivery of large genetic systems splits cargo across vectors, but functional reconstitution depends on stochastic co-delivery and often requires high viral doses. Here, we present a multi-capsid linking strategy that enables coordinated delivery of AAV vectors carrying distinct or split genetic cargos. Using a substrate-confined linking process, we suppress uncontrolled higher-order aggregation while enabling programmable nanoscale capsid coupling via oligonucleotide linkers. These linkers further enable efficient downstream purification of linked AAVs and recycling of unlinked vectors, yielding [~]70% AAV dimers and trimers in <24 hours. By enforcing coordinated delivery, linked AAVs achieve co-transduction at reduced viral doses and with greater expression uniformity than conventional dual-AAV approaches. This improved coordination enhances reconstitution of split genetic systems and increases targeted prime editing efficiency in vitro and in the mouse brain. This capsid coupling strategy expands the functional scope of AAVs toward dose-efficient and uniform delivery of large genetic systems.

bioengineering↗

bioRxiv2026

Targeting Noncanonical TEAD Axis to Overcome DNA Repair-Driven Chemoresistance

How transcription factors contribute to DNA damage repair (DDR) independent of canonical gene regulation remains poorly understood. Here, we show that DNA double-strand break (DSB) triggers a functional state transition in TEAD, disengaging it from YAP-dependent transcription and translocating it to DNA lesions as a chromatin-associated DDR factor. Upon genotoxic stress, TEAD is rapidly recruited to damaged chromatin through a biphasic mechanism involving early poly(ADP-ribose)-dependent recruitment followed by ATM-driven {gamma}H2AX-mediated retention. At DNA lesions, TEAD constrains chromatin over-relaxation, suppresses excessive end resection, and promotes non-homologous end joining (NHEJ) independent of its canonical function. Conserved residues within the TEA domain mediate this noncanonical chromatin engagement of TEAD and define a druggable N-terminal interface. Pharmacological targeting of this interface impaired TEAD-dependent DSB repair and sensitized tumors to chemotherapy. Together, these findings establish noncanonical TEAD as a critical DNA repair factor and a clinically actionable driver of chemoresistance, while providing a conceptual framework for understanding how broader families of transcription factors may be repurposed as targetable DNA damage regulators in cancer.

cancer biology↗