Cell reportsPub Date : 2026-10-12DOI: 10.1016/j.celrep.2026.117997
Joshua Robert Goulding, Stijn Tim Couwenbergh, Sarah-Lee Bekaert, Ellen Sanders, Fanny De Vloed, Vicky Amo-Addae, Aline Eggermont, Jolien De Wyn, Kaat De Wever, Lasse Vleminckx, Selma Eising, Jan J Molenaar, Marlinde L van den Boogaard, Lisa Depestel, Kaat Durinck
{"title":"Pharmacologically targeting CDK12 induces BRCAness and synergizes with merestinib to exacerbate DNA damage in high-risk neuroblastoma.","authors":"Joshua Robert Goulding, Stijn Tim Couwenbergh, Sarah-Lee Bekaert, Ellen Sanders, Fanny De Vloed, Vicky Amo-Addae, Aline Eggermont, Jolien De Wyn, Kaat De Wever, Lasse Vleminckx, Selma Eising, Jan J Molenaar, Marlinde L van den Boogaard, Lisa Depestel, Kaat Durinck","doi":"10.1016/j.celrep.2026.117997","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.117997","url":null,"abstract":"<p><p>High-risk neuroblastoma remains a leading cause of pediatric cancer mortality, underscoring the need for novel therapeutics. MYCN amplification drives transcriptional addiction, creating vulnerabilities for therapeutic intervention. Inhibition of CDK12, a key regulator of transcription elongation, downregulates DNA damage response (DDR) genes. CDK12 inactivation using protein degraders and small molecules, including the orally bioavailable, selective CDK12/13 inhibitor OKI-1546, induced BRCAness and apoptosis in neuroblastoma cells. High-throughput compound screening combined with CDK12 inhibition/degradation revealed synergistic interactions encompassing multiple biological pathways. Merestinib, a multi-kinase inhibitor, emerged as the top synergistic agent across a panel of neuroblastoma in vitro models. Combining OKI-1546 with merestinib amplified DDR downregulation and diminished MYCN-driven signaling. OKI-1546 treatment reduced tumor growth and extended survival in vivo, which was enhanced when combined with merestinib. Whilst further in vivo validation is warranted, our findings nominate CDK12 as a promising therapeutic target in high-risk neuroblastoma, which can be exploited through combinatorial treatments.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"117997"},"PeriodicalIF":7.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2026-10-12DOI: 10.1016/j.celrep.2026.118077
Van La, Abby Trouth, Vijay Ramani, Srinivas Ramachandran
{"title":"Rotational settings quantize nucleosome movement by chromatin regulators.","authors":"Van La, Abby Trouth, Vijay Ramani, Srinivas Ramachandran","doi":"10.1016/j.celrep.2026.118077","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118077","url":null,"abstract":"<p><p>Proper nucleosome positioning is essential for gene regulation and genomic integrity. Current models posit that chromatin regulators override histones' intrinsic sequence preferences to establish nucleosome landscapes observed in vivo, implying a minimal role for DNA sequence in guiding nucleosomal structure. In contrast, we show that DNA sequence intrinsically guides nucleosome structure and remodeling from yeast to mammals. Nucleosomes with weak translational settings in vitro, in yeast, and in mammalian cells display strong rotational positioning that favors inward-facing A/T and outward-facing G/C dinucleotides at 10 bp spacings. Foreign DNA sequences heterologously inserted into the yeast genome obey the same rules, indicating that DNA sequence itself is causal. Remodelers and transcription elongation shift the preference among translational positions 10 bp apart, which maintains the same rotational setting. We propose that DNA sequence creates an energy landscape with preferred rotational settings, and that chromatin regulators navigate within, rather than override, these preferences.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118077"},"PeriodicalIF":7.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2026-10-12DOI: 10.1016/j.celrep.2026.118141
Sol Kim, Luke R Joyce, Amanda Brady, Brady L Spencer, Bradley Pawlikowski, Julia Derk, Kelly S Doran, Julie A Siegenthaler
{"title":"Meningeal inflammation and arachnoid barrier breakdown in a mouse model of neonatal bacterial meningitis.","authors":"Sol Kim, Luke R Joyce, Amanda Brady, Brady L Spencer, Bradley Pawlikowski, Julia Derk, Kelly S Doran, Julie A Siegenthaler","doi":"10.1016/j.celrep.2026.118141","DOIUrl":"10.1016/j.celrep.2026.118141","url":null,"abstract":"<p><p>Newborns are especially susceptible to bacterial meningitis, primarily caused by group B Streptococcus (GBS), due to incomplete maturation of immune and barrier systems. While meningitis is well known to break down the blood-brain barrier, its effect on the meningeal arachnoid barrier remains poorly understood. Using a neonatal bacterial meningitis model, we demonstrate that GBS infection significantly increases arachnoid barrier permeability, disrupts tight junctions, and elevates meningeal production of proinflammatory cytokines. CD206<sup>+</sup>/LYVE-1<sup>+</sup> border-associated macrophages undergo morphological and molecular activation post-infection, but their depletion prior to infection does not attenuate arachnoid barrier leakage or cytokine levels. We show that meningeal fibroblasts are a source of proinflammatory cytokines in response to GBS infection and that a systemic exposure of TNF-α alone is sufficient to induce barrier breakdown. These results support that the neonatal arachnoid barrier is vulnerable to cytokine-induced breakdown and highlight the role of non-immune meningeal cells like fibroblasts during bacterial infection.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118141"},"PeriodicalIF":7.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"EpCAM-dependent membrane mechanics regulate nuclear deformation and promote gastric cancer metastasis.","authors":"Guoqiao Chen, Mengting Jiang, Jing Yang, Xiaolong Liu, Jiaxi Cheng, Qiming Xia, Yixuan Li, Wei Liu, Xiaoxiao Fan, Hui Lin","doi":"10.1016/j.celrep.2026.118126","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118126","url":null,"abstract":"<p><p>Diffuse gastric cancer is highly metastatic and lacks effective therapeutic targets. Using membrane proteomics, gastric cancer cell models, biophysical measurements, and in vivo metastasis assays, we identify EpCAM as a regulator of membrane-cytoskeletal mechanics. EpCAM overexpression was associated with reduced apparent plasma membrane tension, ERM-actin remodeling, increased traction forces, and nuclear deformation. Functional perturbation of ezrin and lamin A/C supported the involvement of membrane-cytoskeleton-nucleus mechanical coupling in confined migration. EpCAM knockout or monoclonal antibody blockade reduced tumor invasion and lymph node dissemination in vivo. These findings establish a mechanobiological framework linking EpCAM-dependent membrane mechanics to metastatic behavior and highlight EpCAM-associated mechanical regulation as a potential therapeutic vulnerability in diffuse gastric cancer.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118126"},"PeriodicalIF":7.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2026-10-12DOI: 10.1016/j.celrep.2026.118081
Philip M Boone, Ricardo Harripaul, Rachita Yadav, Michael Grzybowski, Mahmoud K Hanafy, Amanda C Lee, Esther Y Choi, Ryan L Collins, Oksana Polesskaya, Nina Makhortova, Matthew O Larson, Hakan Kayir, Yizhi Wang, Rodolfo A Avila, Jude A Frie, Amr Eed, Abdalla M Albeely, Sunitha Vemuri, Samantha M Ayoub, John M Lemanski, Daniel Ben-Isvy, Xuefang Zhao, Alba Sanchis-Juan, Maris Handley, Serkan Erdin, Celine de Esch, Kiana Mohajeri, Clementine Chen, Paulina Gonzalez Tovar, Monica Salani, Mariana Moyses-Oliveira, Derek J C Tai, Benjamin Currall, Christopher McGraw, Susan Slaugenhaupt, Ryan Doan, Dadi Gao, James F Gusella, Sandra Sanchez-Roige, Jared W Young, Jibran Y Khokhar, Aron M Geurts, Abraham A Palmer, Michael E Talkowski
{"title":"Aberrant recursive splicing in a human disease locus.","authors":"Philip M Boone, Ricardo Harripaul, Rachita Yadav, Michael Grzybowski, Mahmoud K Hanafy, Amanda C Lee, Esther Y Choi, Ryan L Collins, Oksana Polesskaya, Nina Makhortova, Matthew O Larson, Hakan Kayir, Yizhi Wang, Rodolfo A Avila, Jude A Frie, Amr Eed, Abdalla M Albeely, Sunitha Vemuri, Samantha M Ayoub, John M Lemanski, Daniel Ben-Isvy, Xuefang Zhao, Alba Sanchis-Juan, Maris Handley, Serkan Erdin, Celine de Esch, Kiana Mohajeri, Clementine Chen, Paulina Gonzalez Tovar, Monica Salani, Mariana Moyses-Oliveira, Derek J C Tai, Benjamin Currall, Christopher McGraw, Susan Slaugenhaupt, Ryan Doan, Dadi Gao, James F Gusella, Sandra Sanchez-Roige, Jared W Young, Jibran Y Khokhar, Aron M Geurts, Abraham A Palmer, Michael E Talkowski","doi":"10.1016/j.celrep.2026.118081","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118081","url":null,"abstract":"<p><p>Recursive splice sites are rare motifs postulated to facilitate splicing across massive introns and shape isoform diversity. The necessity of recursive splicing (RS) and its role in human disease are unsubstantiated. Here, we use CRISPR to model intronic deletions eliminating an RS site (RS1) in CADM2 and conferring risk for attention deficit hyperactivity disorder and other neurobehavioral traits. Ablating RS1 in human induced neurons alters the gradient of RNA abundance across CADM2's first intron, decreases CADM2 expression, and impacts transcript usage. Decreased CADM2 expression is reflected in reduced exon usage downstream of RS1 and global alteration to genes involved in neuronal processes. In vivo rodent models harboring Cadm2 RS1 deletions exhibit an attenuated effect on Cadm2 expression and modest changes in behavior and functional brain connectivity. This study demonstrates RS as a noncoding regulatory mechanism in a gene associated with a spectrum of neuropsychiatric and behavioral traits.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118081"},"PeriodicalIF":7.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2026-10-10DOI: 10.1016/j.celrep.2026.118120
Waqas Ahmed, Xiaoyi Li, Ciniso S Shabangu, Hongjie Chen, Nikesh Katuwal, Jennifer Kirchherr, Wenshe R Liu, Xin Li, Yongcheng Song, Kaixiu Luo, H Umit Kaniskan, Jian Jin, Sara Gianella, David M Margolis, Nancie M Archin, Yuyang Tang, Guochun Jiang
{"title":"The ENL-USP7 complex regulates HIV latency through BRD4 protein stabilization.","authors":"Waqas Ahmed, Xiaoyi Li, Ciniso S Shabangu, Hongjie Chen, Nikesh Katuwal, Jennifer Kirchherr, Wenshe R Liu, Xin Li, Yongcheng Song, Kaixiu Luo, H Umit Kaniskan, Jian Jin, Sara Gianella, David M Margolis, Nancie M Archin, Yuyang Tang, Guochun Jiang","doi":"10.1016/j.celrep.2026.118120","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118120","url":null,"abstract":"<p><p>HIV persistence in CD4<sup>+</sup> T cells and brain microglia is maintained by host mechanisms that enforce viral latency. We identify ENL and the deubiquitinase USP7 as a host complex that sustains HIV latency. Pharmacologic inhibition or genetic loss of ENL reactivated latent HIV. Proteomic analyses revealed an ENL-USP7-BRD4 regulatory axis associated with latency maintenance, where USP7 maintained BRD4 protein stability. Targeted USP7 degradation using PROTAC induced latency reversal and destabilized BRD4. Chromatin immunoprecipitation studies showed that ENL was required for USP7 and BRD4 occupancy at the HIV nuc-1 region but not at the 5' long terminal repeat. Single-nucleus RNA sequencing further implicated this pathway in HIV persistence within the central nervous system. Importantly, degradation of either ENL or USP7 reactivated latent HIV in resting CD4<sup>+</sup> T cells and brain microglia from individuals receiving antiretroviral therapy. These findings identify the ENL-USP7-BRD4 axis as a therapeutically actionable mechanism sustaining HIV latency and viral reservoirs.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118120"},"PeriodicalIF":7.7,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Genomic insights into millennia of genetic continuity and trans-regional admixture in the middle-lower Yellow River basin.","authors":"Ziwei Qin, Yuchun Wang, Jianzeng Dai, Shuyi Li, Chaochao Qin, Zhigang Wu, Qu Shen, Yu Qiao, Xuan Zhu, Jingru Zhao, Xingyue Jiang, Yaxin Zhou, Yushen He, Yan Qian, Haifeng He, Le Tao, Hao Ma, Rui Wang, Kongyang Zhu, Yu Xu, Yukai Lin, Chuan-Chao Wang, Zhaohui Yang","doi":"10.1016/j.celrep.2026.118122","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118122","url":null,"abstract":"<p><p>The middle and lower Yellow River regions were crucial for early agricultural development and the emergence of complex societies in East Asia, yet their fine-scale population history from the Neolithic to historical periods remains incompletely resolved. Here, we present genome-wide data from 61 ancient individuals (∼4,500-200 before present [BP]) from Henan and Shandong. Our analyses show that middle-to-late Neolithic populations at Dahecun in Henan are genetically homogeneous and closely related to contemporaneous Yellow River millet-farming populations. By ∼3,000 BP, Shandong populations shift toward a late Neolithic middle Yellow River-related ancestry profile, consistent with the eastward expansion of middle Yellow River agricultural populations. This ancestry profile persists into historical periods, indicating long-term genetic continuity in Shandong. Two Tang-Song-period individuals from western Shandong carry ∼15% West Eurasian-related ancestry, indicating limited cross-regional genetic interaction. These findings refine the population history of the middle and lower Yellow River regions.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118122"},"PeriodicalIF":7.7,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2026-10-10DOI: 10.1016/j.celrep.2026.118118
Marzieh Daniali, Breana Channer, Erin O Curley, Amirali Amirfallah, Taylor Kist, John Montilla Luna, Stephanie Kosashvili, Lexi Sheldon, Kelly Stauch, Joshua G Jackson, Anneliese M Faustino, Thomas Beer, Hsin-Yao Tang, Stephanie M Matt, Will Dampier, Howard Fox, Peter J Gaskill
{"title":"Dopamine-induced mitochondrial dysfunction activates cGAS-sTING to drive IL-6 secretion in macrophages.","authors":"Marzieh Daniali, Breana Channer, Erin O Curley, Amirali Amirfallah, Taylor Kist, John Montilla Luna, Stephanie Kosashvili, Lexi Sheldon, Kelly Stauch, Joshua G Jackson, Anneliese M Faustino, Thomas Beer, Hsin-Yao Tang, Stephanie M Matt, Will Dampier, Howard Fox, Peter J Gaskill","doi":"10.1016/j.celrep.2026.118118","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118118","url":null,"abstract":"<p><p>Despite growing evidence that dopamine acts as an innate immune inflammatory mediator, the molecular mechanisms by which dopamine modulates human immune function are incompletely defined. Here, we define the pathway in which dopamine induces robust IL-6 secretion in primary human monocyte-derived macrophages (hMDMs) through mitochondrial stress. Dopamine initiates a transient mitochondrial membrane depolarization that leads to sustained alterations in mitochondrial dynamics, including morphology and metabolism. These events promote the release of mtDNA into the cytoplasm, triggering the cGAS-STING pathway and NF-κB signaling. Pharmacological inhibition at multiple nodes of this pathway attenuates IL-6 secretion, establishing mitochondrial dysfunction and cGAS-STING signaling as central mediators of dopamine-driven IL-6 secretion. Variability in dopamine receptor expression across donors correlates with the magnitude of IL-6 responses. These findings highlight a potential link between dopamine signaling and systemic inflammation and suggest that differences in dopamine receptor expression may contribute to inter-individual variation in innate immune responses.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118118"},"PeriodicalIF":7.7,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2026-10-09DOI: 10.1016/j.celrep.2026.118085
Wanchao Hu, Geraldine Schlecht-Louf, Camille Vielhescaze, Nicolas Trainel, Solène Jouvanceau, Aurore Desmons, Françoise Mercier-Nomé, Sophie Viel, Aboubacar Sidiki K Coulibaly, Clara Perrin, Charlotte Canet-Jourdan, Ana-Maria Lennon-Duménil, Gerard Eberl, Gabriel Perlemuter, Dragos Ciocan, Anne-Marie Cassard
{"title":"Pectin alleviates alcohol-associated liver disease partly through cell-type-specific aryl hydrocarbon receptor signaling in female mice.","authors":"Wanchao Hu, Geraldine Schlecht-Louf, Camille Vielhescaze, Nicolas Trainel, Solène Jouvanceau, Aurore Desmons, Françoise Mercier-Nomé, Sophie Viel, Aboubacar Sidiki K Coulibaly, Clara Perrin, Charlotte Canet-Jourdan, Ana-Maria Lennon-Duménil, Gerard Eberl, Gabriel Perlemuter, Dragos Ciocan, Anne-Marie Cassard","doi":"10.1016/j.celrep.2026.118085","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118085","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AhR) plays a critical role in alcohol-associated liver disease (ALD). Pectin improves ALD partially through the AhR pathway. However, AhR is expressed across different organs and cell types, and the specific cellular targets mediating AhR's effects in ALD remain unclear. We generated conditional AhR knockout mice in intestinal epithelial cells, hepatocytes, dendritic cells, and Rorγt-positive cells, in which AhR may play a critical role in regulating the gut-liver axis and pectin protection against ALD. ALD was induced using the Lieber-DeCarli model, and mice received pectin supplementation. AhR deficiency in intestinal epithelial cells and hepatocytes in mice leads to increased hepatic inflammation and serum ALT following alcohol administration compared with their littermate controls. However, pectin exerted strong protective effects against ALD in all the models. Our results suggest that AhR activation across multiple cell types, rather than a single cell type, mediates the protective role of pectin.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118085"},"PeriodicalIF":7.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2026-10-09DOI: 10.1016/j.celrep.2026.118109
Lily Thompson, Rim Nassar, Annapaola Angrisani, Owen Ou Ning Hsiu, Yian Yang, Katarzina M Kedziora, Daniela Muoio, Rhea Gupta, Daniele Fachinetti, Wayne Stallaert, Elise Fouquerel
{"title":"Oxidative DNA damage drives centromere fragility and chromosome instability.","authors":"Lily Thompson, Rim Nassar, Annapaola Angrisani, Owen Ou Ning Hsiu, Yian Yang, Katarzina M Kedziora, Daniela Muoio, Rhea Gupta, Daniele Fachinetti, Wayne Stallaert, Elise Fouquerel","doi":"10.1016/j.celrep.2026.118109","DOIUrl":"10.1016/j.celrep.2026.118109","url":null,"abstract":"<p><p>Centromeres are essential regions of the genome that ensure chromosome segregation during mitosis but are also hotspots for chromosome breaks and rearrangements in cancer. The mechanisms underlying this fragility are not fully elucidated. Here, we show that oxidative DNA damage destabilizes centromeres and promotes chromosome instability. Using a chemoptogenetic system to generate singlet oxygen locally at centromeres, we uncouple centromeric oxidative damage from global oxidative stress. Oxidative base lesions slow DNA synthesis, destabilize CENP-A chromatin, and generate DNA breaks that persist into subsequent cell cycles. Single-cell time-lapse imaging reveals cell-cycle-dependent outcomes, with lesions before or during replication favoring quiescence and post-replicative lesions allowing mitotic progression but compromising daughter-cell proliferation. Finally, in pre-tumorigenic cells, centromeric oxidative lesions lead to mitotic defects, aneuploidy, and whole-arm chromosome translocations. Collectively, we identify centromeres as cell-cycle-sensitive DNA damage sensors and oxidative stress as a direct driver of centromere fragility and chromosome instability.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118109"},"PeriodicalIF":7.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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