Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"Structural diversity of full-length human αvβ3 integrin revealed by cryo-EM","authors":"Cang Wu ,&nbsp;Yuanzhu Gao ,&nbsp;Weiyan Wang ,&nbsp;Zhoufang Li ,&nbsp;Qing Shu ,&nbsp;Xi Zhang","doi":"10.1016/j.bbamcr.2025.120089","DOIUrl":"10.1016/j.bbamcr.2025.120089","url":null,"abstract":"<div><div>Integrins are essential transmembrane receptors that orchestrate cell adhesion, migration, and survival, and have emerged as promising therapeutic targets for cancer, fibrosis, and autoimmune diseases. However, most integrin-targeted drugs have failed in clinical trials due to limited efficacy and unexpected off-target effects, reflecting an incomplete understanding of integrin conformational regulation. Here, we present a series of high-resolution cryo-EM structures of human integrin αvβ3 in both apo and ligand-bound states by collecting a large amount of data. Consequently, we resolved six conformations of integrin in the apo state, five of which were previously uncharacterized, along with five distinct ligand-bound states, thereby revealing a continuum of conformational transitions underlying integrin activation. Notably, CWHM-12 enables the simultaneous coexistence of integrin in closing and opening inhibited states, revealing a mechanism that differs fundamentally from that of conventional RGD peptide-based inhibitors. Then, our study provides a structural framework for understanding integrin activation diversity and lays the foundation for rational design of next-generation inhibitors with improved precision and reduced off-target effects.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120089"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained Galiellalactone treatment breaks the metastatic resilience of BRAF-inhibitor-resistant melanoma cells","authors":"Sujoy Bhowmik,&nbsp;Saumya Ranjan Badajena ,&nbsp;Satyajit Laxman Murkute ,&nbsp;Dumarapu Bhagyalaxmi,&nbsp;Purusottam Mohapatra","doi":"10.1016/j.bbamcr.2025.120096","DOIUrl":"10.1016/j.bbamcr.2025.120096","url":null,"abstract":"<div><div>STAT3 hyperactivation in metastatic and therapy-resistant melanoma drives tumorigenesis and immunotherapy resistance by promoting tumor-stromal interactions, making its inhibition a crucial therapeutic strategy. Interestingly, synthetic STAT3 inhibitors could not manage to enter clinical trials due to their short half-lives, poor bioavailability and non-specific effects. Here, we have shown that Galiellalactone, a natural, irreversible STAT3 inhibitor, blocks IL-6 and WNT5A-mediated STAT3 Phosphorylation and migration in BRAF-inhibitor (BRAFi)-sensitive melanoma cells. Galiellalactone treatment leads to prolonged STAT3 inhibition, which obstructs both metastatic functions and secretome-mediated paracrine interactions in both BRAFi-sensitive and resistant melanoma cells, <em>via</em> the reduction of MCAM and N-cadherin protein expression. Altogether, our findings support that Galiellalactone is a potential inhibitor that could block the metastatic function of drug-resistant melanoma cells and also obstruct the possible paracrine activation of STAT3 conferred by stromal cells present in the tumor microenvironment.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120096"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145734743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of YBX1 and JAK2/STAT3 pathways by RIOK1 increases lenvatinib resistance in hepatocellular carcinoma cells","authors":"Ruirui Cao ,&nbsp;Yue Wu ,&nbsp;Yawei Li ,&nbsp;Mengting Shi ,&nbsp;Tiantian Zhang ,&nbsp;Weijie Sun ,&nbsp;Yang Liu ,&nbsp;Rui Wang","doi":"10.1016/j.bbamcr.2025.120094","DOIUrl":"10.1016/j.bbamcr.2025.120094","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is fatal and does not respond well to classical chemotherapies. This paper investigates the molecular mechanism of RIOK1 on lenvatinib resistance in HCC cells. Differentially expressed genes were identified before and after lenvatinib treatment using transcriptome sequencing. Lenvatinib resistance in HCC cells was detected. The interaction between RIOK1 and YBX1 was assessed. YBX1, JAK2, and STAT3 phosphorylation levels were detected. The effect of YBX1 and JAK2/STAT3 pathway activator on lenvatinib resistance was analyzed. Tumor volume and weight, and apoptosis were analyzed in lenvatinib-treated nude mice. RIOK1, YBX1, and JAK2/STAT3 were reduced in HCC cells after lenvatinib treatment. RIOK1 knockdown prevented HCC cell growth and reduced lenvatinib resistance. The interaction between RIOK1 and YBX1 induced Ser 165 phosphorylation, thereby promoting nuclear localization of YBX1. YBX1, JAK2, and STAT3 phosphorylation levels were elevated upon RIOK1 overexpression. YBX1 overexpression and JAK2/STAT3 pathway activator mitigated the anticancer effect of RIOK1 knockdown and increased lenvatinib resistance. Tumor volume, apoptosis, KI67, YBX1, and JAK2/STAT3 phosphorylation levels were reduced in tumor tissue after RIOK1 knockdown and increased after further YBX1 overexpression. Overall, RIOK1 activates the JAK2/STAT3 pathway by promoting YBX1 phosphorylation, leading to HCC progression and lenvatinib resistance.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120094"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteocyte transition induced by quiescent vascular smooth muscle cells through paracrine signaling is independent of shear stress","authors":"Célio J.C. Fernandes ,&nbsp;Bram C.J. van der Eerden ,&nbsp;Rodrigo A. Foganholi Silva ,&nbsp;Gwenny M. Fuhler ,&nbsp;Maikel P. Peppelenbosch ,&nbsp;Willian F. Zambuzzi","doi":"10.1016/j.bbamcr.2025.120092","DOIUrl":"10.1016/j.bbamcr.2025.120092","url":null,"abstract":"<div><div>We investigated how vascular smooth muscle cells (VSMCs) shape osteolineage fate under mechanosignaling, with emphasis on validating effects in mesenchymal stromal cells (MSCs), a more primitive stage than differentiated osteoblasts. Conditioned media from shear-stressed and non-stressed VSMCs challenged primary human osteoblasts and human MSCs for up to 28 days. Across both cell types, VSMCs robustly promoted osteoblast-to-osteocyte plasticity, evidenced by morphological remodeling and increased expression of osteocyte markers (GP38, SOST, DMP1, miR-23a, FGF23). Notably, non-stressed VSMC–conditioned medium elicited stronger osteocyte-function signatures, including a &gt; 10-fold rise in RANKL transcripts, and these responses were recapitulated in MSCs, demonstrating that VSMC cues instruct osteogenic commitment at an earlier lineage stage and converge on an osteocyte-like phenotype. Mechanistically, small extracellular vesicles (sEVs) emerged as key mediators of VSMC–bone crosstalk: sEV cargo from non-stressed VSMCs displayed higher SOST and DMP1 transcripts, along with phosphor - β-catenin, phospho-connexin-43, and ATP, suggesting pathways that support osteocyte survival and function. Collectively, our data position VSMCs as pivotal instructors of osteolineage progression - from MSC commitment to osteocyte specification - via sEV-dependent communication, with non-stressed VSMCs exerting the strongest effect, particularly on functional readouts such as RANKL. Further, these findings support VSMC-sEV–inspired, cell-free approaches to modulate osteocytogenesis and regulate bone remodeling, while proposing SOST/DMP1/miR-23a as candidate circulating markers of osteocyte function and treatment response.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120092"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cationic liposome-based silencing of thioredoxin reductase-1 for sensitization of MDA-MB 231 cells to gamma radiation","authors":"Sandeep B. Shelar ,&nbsp;Manidipa Basu ,&nbsp;P.A. Hassan ,&nbsp;K.C. Barick","doi":"10.1016/j.bbamcr.2025.120100","DOIUrl":"10.1016/j.bbamcr.2025.120100","url":null,"abstract":"<div><div>Thioredoxin reductase 1 (TrxRd1) is a widely conserved antioxidant enzyme that maintains cellular redox homeostasis by reducing oxidized thioredoxin 1 (Trx1). Overexpression of TrxRd1 has been directly linked to radioresistance in cancer cells. In this study, we examined the impact of cationic liposome-mediated knockdown of TrxRd1 on the radiosensitization of MDA-MB 231 breast cancer cells. Cationic liposomes were formulated using dihexadecyldimethylammonium bromide (DDAB) as a surfactant and soy lecithin as the lipid component, employing a supercooled micelle-based method. These liposomes were complexed with plasmid DNA encoding a short hairpin RNA targeting TrxRd1 (shTrxRd1) via electrostatic interactions. Lipoplex formation (DDAB-shTrxRd1) was confirmed by assessing changes in hydrodynamic size, surface charge, and isothermal titration calorimetry. Cellular uptake was demonstrated by cytosolic localization of propidium iodide (PI) and expression of green fluorescent protein (GFP), while reduced TrxRd1 mRNA levels confirmed gene silencing. TrxRd1 knockdown led to elevated reactive oxygen species (ROS) levels in gamma-irradiated cells. This was accompanied by decreased cell viability, reduced colony formation, and increased apoptosis, indicating enhanced radiosensitization of MDA-MB 231 cells following TrxRd1 suppression and gamma radiation exposure. In summary, targeting TxrRd1 by cationic liposome gene silencing provide improved radiosensitization of breast cancer cells through augmenting ROS accumulation.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120100"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ephrin-A1/EphA2 modulates vascular smooth muscle cell proliferation in vitro, while VSMC-specific ephrin-A1 deletion is not sufficient to alter arteriosclerosis in vivo","authors":"Antje Augstein ,&nbsp;Sebastian Porth ,&nbsp;Johannes Mierke ,&nbsp;Janet Friedrich ,&nbsp;Stefanie Jellinghaus ,&nbsp;Axel Linke ,&nbsp;Volker Adams ,&nbsp;David M. Poitz","doi":"10.1016/j.bbamcr.2025.120098","DOIUrl":"10.1016/j.bbamcr.2025.120098","url":null,"abstract":"<div><div>Atherosclerosis, the leading cause of heart attack and stroke, involves plaque formation driven by various cell types, including endothelial cells, immune cells and vascular smooth muscle cells (VSMCs). VSMCs undergo a phenotypic switch from a contractile to a synthetic state, contributing to disease progression. The Eph/ephrin signaling pathway, particularly ephrin-A1 and its receptor EphA2, has been implicated in this phenotypic modulation. Its role in atherosclerosis was explored using <em>in vitro</em> and <em>in vivo</em> models.</div><div>In plaque-containing arteries, both ephrin-A1 and EphA2 were upregulated compared to plaque-free regions. The phenotypic transition of VSMCs from a contractile to a synthetic state is associated with reduced ephrin-A1 levels, elevated EphA2 expression, and increased cellular proliferation. A consistent expression pattern with low ephrin-A1 and high EphA2 was observed in proliferating cells. Additionally, under pro-proliferative conditions, the non-canonical phosphorylation site S897/898 of EphA2 is phosphorylated in a MEK/ERK/RSK-dependent manner, while the canonical site Y588/589 undergoes autophosphorylation at higher ephrin-A1 levels. These <em>in vitro</em> findings suggest an anti-proliferative, potentially anti-atherogenic role for ephrin-A1 in VSMCs. This hypothesis was further examined in ApoE-KO mice using a conditional VSMC-specific ephrin-A1 knockout. Surprisingly, neither high-fat diet-induced atherosclerosis nor wire injury-induced stenosis differed between ephrin-A1-deficient and wild-type mice, implying functional compensation by other ephrin ligands.</div><div>The present findings highlight significant roles for the Eph/ephrin system in VSMC biology and plaque development. However, its effects appear to be multimodal, influenced by the interplay between various cell types and distinct members of the Eph/ephrin family.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120098"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RelK, a YoeB-like toxin from Mycobacterium tuberculosis displays ribosome independent endonucleolytic activity","authors":"Shafinaz Rahman Sarah ,&nbsp;Nimisha Sinha ,&nbsp;Harsh A. Gandhi ,&nbsp;Jaydeep Bhattacharya ,&nbsp;Vandana Malhotra","doi":"10.1016/j.bbamcr.2025.120097","DOIUrl":"10.1016/j.bbamcr.2025.120097","url":null,"abstract":"<div><div>Type II toxin-antitoxin (TA) modules are paired genetic elements encoding a toxin protein and an associated antitoxin that neutralizes the toxin under favourable growth conditions. Stress-induced degradation of the antitoxin renders the toxin free to disrupt essential cellular processes leading to growth arrest or cell death. <em>Mycobacterium tuberculosis (M. tb)</em> is known to harbor 60+ such modules that contribute to its pathogenicity and persistence. The RelK toxin of the RelJK cassette has generated significant interest given its expression during infection and regulation by post-translational modification; however, its functional activity remains uncharacterized. Using a cell free transcription-translation system we show that both, unphosphorylated and phosphorylated RelK toxin inhibit <em>in vitro</em> protein synthesis implicating a role in translational control, one that is enhanced by S/T phosphorylation. A key finding of this study is the ribosome-independent nuclease activity of RelK. We discovered that in addition to the <em>in vitro</em> RNase activity, RelK also cleaves double-stranded DNA in a dose-dependent manner, and is inactivated by the RelJ antitoxin. Further characterization established RelK as a nickase whose activity is modulated by divalent cations, and is independent of the substrate topology, although supercoiled DNA substrates are preferred. Molecular docking of RelK revealed multiple contacts with the phosphate backbone and bases of the dsDNA facilitating binding and protein orientation on the major groove region. Furthermore, substituting His84 with glutamine in RelK not only abolished its catalytic activity but also obliterated cytotoxicity. The data highlights the diversity in substrates and catalytic activities of <em>M. tb</em> Type II toxins.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120097"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone methyltransferase NSD3 orchestrates early erythropoiesis by regulating erythroid progenitor cell differentiation and survival","authors":"Arunim Shah ,&nbsp;Shobhita Katiyar ,&nbsp;Chandra Prakash Chaturvedi ,&nbsp;Bhuvnesh Rai ,&nbsp;Khaliqur Rahman ,&nbsp;Naresh Tripathy ,&nbsp;Sanjeev Yadav ,&nbsp;Anshul Gupta","doi":"10.1016/j.bbamcr.2025.120095","DOIUrl":"10.1016/j.bbamcr.2025.120095","url":null,"abstract":"<div><div>Histone methyltransferase <em>NSD3</em> also known <em>KMT3F,</em> is an epigenetic regulator that methylates histone H3 at lysine 36, a mark associated with gene activation. Functionally, NSD3 is crucial for supporting various cellular and developmental processes, and its deregulation can lead to various disease conditions, including solid and hematological cancers. However, the role of NSD3 in regulating normal hematopoiesis remains elusive. In the present study, we have investigated the role of NSD3 in regulating human erythropoiesis, the process of red blood cell production from hematopoietic stem cells (HSCs). To achieve this, we isolated CD34⁺ HSCs from a healthy donor and subjected them to ex-vivo erythroid differentiation. Using a combination of lentiviral transduction and small hairpin RNA-mediated knockdown approaches, we targeted NSD3 depletion during the early phases of erythroid differentiation. Our results demonstrated that depleting NSD3 on days 2 and 7 of ex-vivo erythroid differentiation resulted in notable disruptions of erythropoiesis process. Specifically, NSD3 downregulation resulted in a decreased megakaryocyte-erythroid progenitors, reduced colony formation, and a significant decrease in erythroid differentiation markers. Furthermore, NSD3 depletion altered erythroid differentiation by favouring basophilic erythroblasts over ortho/polychromatic erythrocytes. At the transcriptomic level, <em>NSD3</em> depletion led to the downregulation of key hematopoiesis-specific transcription factors and genes associated with erythroid differentiation and hemoglobin synthesis. Additionally, NSD3 depletion also induced apoptosis and hindered cell proliferation, accompanied by altered expression of genes involved in these pathways. Our findings uncover a previously undescribed role of histone methyltransferase NSD3 in regulating human erythropoiesis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120095"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tumor suppressor role of mitochondrial E3 ubiquitin ligase MUL1 in osteosarcoma","authors":"Jacopo Di Gregorio ,&nbsp;Sara Terreri ,&nbsp;Michela Rossi ,&nbsp;Giulia Battafarano ,&nbsp;Laura Di Giuseppe ,&nbsp;Olivia Pagliarosi ,&nbsp;Lucia Cilenti ,&nbsp;Enrico Ricevuto ,&nbsp;Antonis S. Zervos ,&nbsp;Vincenzo Flati ,&nbsp;Andrea Del Fattore","doi":"10.1016/j.bbamcr.2025.120101","DOIUrl":"10.1016/j.bbamcr.2025.120101","url":null,"abstract":"<div><div>Osteosarcoma is a highly aggressive type of bone cancer with a high rate of metastasis. The molecular mechanisms underlying osteosarcoma metastasis are not yet completely understood, representing an ongoing challenge for therapy. A possible therapeutic target is the hypoxia-inducible factor HIF-1α which is upregulated in metastatic osteosarcoma. Indeed, HIF-1α promotes proliferation, resistance to apoptosis and metabolic reprogramming towards glycolysis, whereas its downregulation increases apoptosis. The molecular mechanism mediated by the mitochondrial E3 ubiquitin ligase MUL1 could be exploited to target HIF-1α since low MUL1 protein levels result in HIF-1α accumulation and activity even under normoxic conditions, while high levels of MUL1 promote HIF-1α degradation. Here, we show that MUL1 protein levels inversely correlate with the aggressiveness of osteosarcoma cell lines. Induction of MUL1 in aggressive cells reduces HIF-1α levels, paired with a decrease in proliferation, migration and glycolysis and increase in apoptosis, whereas MUL1 inactivation in low-aggressive cells has opposite results. Therefore, the modulation of MUL1 protein levels affects cell proliferation, migration, apoptosis, and metabolism. This is the first report that reveals a tumor suppressor role for MUL1 in osteosarcoma, and suggests MUL1 induction as a potential therapeutic strategy to reduce HIF-1α activity in the metastatic progression of this cancer.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120101"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145861420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor suppressor collateral damage screens reveal mRNA homeostasis protein HBS1L as a novel vulnerability in ch9p21 driven FOCAD deleted cancer","authors":"Hongxiang Zhang,&nbsp;Matthew R. Tonini,&nbsp;Lauren Catherine M. Martires,&nbsp;Helena N. Jenkins,&nbsp;Charlotte B. Pratt,&nbsp;Eden N. Gordon,&nbsp;Shanchuan Zhao,&nbsp;Ashley H. Choi,&nbsp;Samuel R. Meier,&nbsp;Tenzing Khendu,&nbsp;Shangtao Liu,&nbsp;Binzhang Shen,&nbsp;Hannah Stowe,&nbsp;Katerina Pashiardis,&nbsp;Xuewen Pan,&nbsp;Madhavi Bandi,&nbsp;Minjie Zhang,&nbsp;Yi Yu,&nbsp;Chengyin Min,&nbsp;Alan Huang,&nbsp;Teng Teng","doi":"10.1016/j.bbamcr.2025.120070","DOIUrl":"10.1016/j.bbamcr.2025.120070","url":null,"abstract":"<div><div>Chromosomal deletion of tumor suppressor genes often occurs in an imprecise manner, leading to co-deletion of neighboring genes. This collateral damage can create novel dependencies specific to the co-deleted context. One notable example is the dependency on PRMT5 activity in tumors with <em>MTAP</em> deletion, which co-occurs with <em>CDKN2A/B</em> loss, leading to the development of MTA-cooperative PRMT5 inhibitors. To identify additional collateral damage context/target pairs for chromosome 9p and other common loci of chromosomal deletions, we conducted a combinatorial CRISPR screen knocking out frequently co-deleted genes in combination with a focused target library. We identified the gene encoding the ribosome rescue factor PELO as synthetic lethal with the SKI complex interacting exonuclease FOCAD, which is frequently co-deleted alongside <em>MTAP</em> and <em>CDKN2A/B</em> on chromosome 9p. A genome-wide screen in <em>FOCAD</em> isogenic cells further identified the ribosome rescue GTPase and PELO binding partner HBS1L as the top synthetic lethal target for <em>FOCAD</em> loss. Analysis of publicly available data and genetic manipulation of <em>HBS1L</em> using orthogonal modalities validated this interaction. HBS1L dependency in <em>FOCAD</em>-deleted cells was rescued by <em>FOCAD</em> re-expression, and <em>FOCAD</em> intact cells could be rendered HBS1L-dependent by <em>FOCAD</em> knockout, demonstrating the context specificity of this interaction. Mechanistically, <em>HBS1L</em> loss led to translational arrest and activated the unfolded protein response in <em>FOCAD</em>-deleted cells. <em>In vivo</em>, <em>HBS1L</em> deletion eliminated growth of <em>FOCAD</em>-deleted tumors. Here we propose a model where the FOCAD/SKI complex and HBS1L/PELO work together to resolve aberrant mRNA-induced ribosomal stalling, making the HBS1L/PELO complex an intriguing novel target for treating <em>FOCAD</em>-deleted tumors.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 1","pages":"Article 120070"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}