Cell Death & Disease最新文献

{"title":"SET8 inhibition preserves PTEN to attenuate kidney cell apoptosis in cisplatin nephrotoxicity.","authors":"Xu Yang, Yingjie Guan, George Bayliss, Ting C Zhao, Shougang Zhuang","doi":"10.1038/s41419-025-07526-y","DOIUrl":"10.1038/s41419-025-07526-y","url":null,"abstract":"<p><p>The aberrant expression of SET8, a histone methyltransferase that mediates H4 lysine 20 mono-methylation (H4K20me1), is implicated in the pathogenesis of various tumors, however, its role in acute kidney injury (AKI) is unknown. Here, we showed that SET8 and H4K20me1 were upregulated in the murine kidney with AKI induced by cisplatin, along with increased renal tubular cell injury and apoptosis and decreased expression of E-cadherin and Phosphatase and Tensin Homolog (PTEN). Suppression of SET8 by UNC0379 improved renal function, attenuated tubule damage, and restored expression of PTEN but not E-cadherin. UNC0379 was also effective in lessening cisplatin-induced DNA damage response (DDR) as indicated by reduced expression of γ-H2AX, p53, p21, and alleviating cisplatin-impaired autophagy as shown by retained expression of Atg5, Beclin-1, and CHMP2A and enhanced levels of LC3-II in the kidney. Consistently, inhibition of SET8 with either UNC0379 or siRNA mitigated apoptosis and DDR and restored autophagy, along with PTEN preservation in cultured renal proximal tubular epithelial cells (TKPTs) exposed to cisplatin. Further studies showed that inhibition of PTEN with Bpv or siRNA potentiated cisplatin-induced apoptosis and DDR, hindered autophagy, and conversely, alleviated by overexpression of PTEN in TKPTs. Finally, blocking PTEN largely abolished the inhibitory effect of UNC0379 on apoptosis. Taken together, these results suggest that SET8 inhibition protects against cisplatin-induced AKI and renal cell apoptosis through a mechanism associated with the preservation of PTEN, which in turn inhibits DDR and restores autophagy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"226"},"PeriodicalIF":8.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11958763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRF2 interaction with nuclear envelope is required for cell polarization and metastasis in triple negative breast cancer.","authors":"Eleonora Petti, Serena Di Vito, Roberto Dinami, Manuela Porru, Stefano Marchesi, Jeroen Lohuis, Pasquale Zizza, Sara Iachettini, Erica Salvati, Carmen D'Angelo, Angela Rizzo, Carmen Maresca, Flora Ascione, Anna Di Benedetto, Simonetta Buglioni, Andrea Sacconi, Paola Ostano, Qingsen Li, Antonella Stoppacciaro, Carlo Leonetti, Jacco van Rheenen, Paolo Maiuri, Giorgio Scita, Annamaria Biroccio","doi":"10.1038/s41419-025-07415-4","DOIUrl":"10.1038/s41419-025-07415-4","url":null,"abstract":"<p><p>The Telomere Repeat-Binding factor 2 (TRF2) contributes to cancer progression by both telomere-dependent and independent mechanisms, including immune escape and angiogenesis. Here, we found that TRF2, through its Basic domain, directly interacts with Emerin forming a complex, including Lamin A/C, Lamin B1, SUN1, and SUN2. Importantly, TRF2 association with the inner nuclear membrane is functional to the proper establishment of cell polarity, finally promoting productive 1D and 3D migration in triple negative breast cancer cells (TNBC). In line with this, a spontaneous model of TNBC metastasis, combined with intravital imaging, allowed us to demonstrate that TRF2 promotes cell migration at the primary tumor site and is required for the early steps of the metastatic cascade. In human breast cancers, aberrantly elevated TRF2 expression positively correlates with cancer progression, metastasis, and poor prognosis, identifying TRF2 as a potential target for novel therapeutic strategies against TNBC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"224"},"PeriodicalIF":8.1,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11955551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytoplasmic accumulation of a splice variant of hnRNPA2/B1 contributes to FUS-associated toxicity in a mouse model of ALS.","authors":"S Rossi, M Milani, I Della Valle, S Bisegna, V Durante, M Addesse, E D'Avorio, M Di Salvio, A Serafino, G Cestra, S Apolloni, N D'Ambrosi, M Cozzolino","doi":"10.1038/s41419-025-07538-8","DOIUrl":"10.1038/s41419-025-07538-8","url":null,"abstract":"<p><p>Genetic and experimental findings point to a crucial role of RNA dysfunction in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Evidence suggests that mutations in RNA binding proteins (RBPs) such as FUS, a gene associated with ALS, affect the regulation of alternative splicing. We have previously shown that the overexpression of wild-type FUS in mice, a condition that induces ALS-like phenotypes, impacts the splicing of hnRNP A2/B1, a protein with key roles in RNA metabolism, suggesting that a pathological connection between FUS and hnRNP A2/B1 might promote FUS-associated toxicity. Here we report that the expression and distribution of different hnRNP A2/B1 splice variants are modified in the affected tissues of mice overexpressing wild-type FUS. Notably, degenerating motor neurons are characterized by the cytoplasmic accumulation of splice variants of hnRNP A2/B1 lacking exon 9 (hnRNP A2b/B1b). In vitro studies show that exon 9 skipping affects the nucleocytoplasmic distribution of hnRNP A2/B1, promoting its localization into stress granules (SGs), and demonstrate that cytoplasmic localization is the primary driver of hnRNP A2b recruitment into SGs and cell toxicity. Finally, boosting exon 9 skipping using splicing switching oligonucleotides exacerbates disease phenotypes in wild-type FUS mice. Altogether, these findings reveal that alterations of the nucleocytoplasmic distribution of hnRNP A2/B1, driven by FUS-induced splicing changes, likely contribute to motor neuron degeneration in ALS.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"219"},"PeriodicalIF":8.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SERPINA3 predicts long-term neurological outcomes and mortality in patients with intracerebral hemorrhage.","authors":"Pei Zheng, Zhihui Qi, Bin Gao, Yang Yao, Jingshan Chen, Hengri Cong, Yue Huang, Fu-Dong Shi","doi":"10.1038/s41419-025-07551-x","DOIUrl":"10.1038/s41419-025-07551-x","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and disability rates, and long-term outcomes among survivors remain unpredictable due to the lack of reliable biomarkers. In this study, spatial transcriptomics was used to analyze molecular profiles in autopsy brain tissues from chronic ICH patients, revealing distinct transcriptomic features in the thalamus and cortex, with common inflammatory characteristics such as gliosis, apoptosis, and immune activation. Serine proteinase inhibitor NA3 (SERPINA3) was significantly upregulated in both regions and co-expressed with astrocytes in the thalamus. Pathological studies in postmortem human tissues and mouse models confirmed elevated SERPINA3 expression, with murine Serpina3n showing a similar pattern in mice. Plasma analysis of 250 ICH patients and 250 healthy controls revealed significantly higher SERPINA3 levels in ICH patients, correlating with hemorrhage severity, National Institutes of Health Stroke Scale (NIHSS), and Glasgow Coma Scale (GCS) scores, and long-term functional outcomes. Higher SERPINA3 levels within 72 hours of hemorrhage onset were independently associated with worse functional recovery (mRS ≥ 3) and increased all-cause mortality at 6 and 12 months. Additionally, SERPINA3 levels at 7 days post-ictus correlated with white matter hyperintensities and poor cognitive performance at 6 months. These findings highlight SERPINA3 as a potential prognostic biomarker for ICH, warranting further investigation into its role in long-term neurological dysfunction and validation in larger prospective cohorts.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"218"},"PeriodicalIF":8.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gastroesophageal circulating tumor cell crosstalk with peripheral immune system guides CTC survival and proliferation.","authors":"Tania Rossi, Martina Valgiusti, Maurizio Puccetti, Giacomo Miserocchi, Michele Zanoni, Davide Angeli, Chiara Arienti, Ilaria Pace, Cristian Bassi, Ivan Vannini, Mattia Melloni, Erika Bandini, Milena Urbini, Massimo Negrini, Massimiliano Bonafè, Manuela Ferracin, Giulia Gallerani","doi":"10.1038/s41419-025-07530-2","DOIUrl":"10.1038/s41419-025-07530-2","url":null,"abstract":"<p><p>Tumor dissemination is a key event in tumor progression. During this event, a main role is played by circulating tumor cells (CTCs), immune cells, and their interaction. How the immune system supports the survival and proliferation of CTCs is not fully elucidated. In this study we established an in-vitro co-culture system consisting of immune cells and CTCs from the same patient, which increased the success rate in the establishment of CTC-derived long-term cell cultures. In this system, we characterized the immune cells of successful co-cultures and the signals they exchange with cancer cells, including cytokines and extracellular vesicle (EV) content. Using this protocol, we stabilized four CTC-derived cell lines from patients with metastatic gastroesophageal cancer, which were cultured for over a year and characterized from a genetic and molecular point of view. The four cell lines harbor shared chromosomal aberrations including the amplification at 8q24.21 containing MYC and deletion 9p21.3 containing CDKN2A/B and the IFN type I cluster. The transcriptomic profile of CTC cell lines is distinct from primary tumors, and we detected the activation of E2F, G2M and MYC pathways and the downregulation of interferon response pathway. Each cell line shows a degree of invasiveness in zebrafish in-vivo, and the most invasive ones share the same mutation in RAB14 gene. In addition, the four cell lines secrete cell-line specific EVs containing microRNAs that target YAP, BRG1-AKT1, TCF8-HDAC pathways. Overall, we highlight how the immune system plays a key role in the proliferation of CTCs through EV signaling, and how CTC cell line genomic and transcriptomic alterations make these cells less visible from the immune system and likely responsible for the survival advantage in sites distant from the microenvironment of origin.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"223"},"PeriodicalIF":8.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA N⁶-methyladenosine demethylase FTO promotes diabetic wound healing through TRIB3-mediated autophagy in an m⁶A-YTHDF2-dependent manner.","authors":"Zheng Dong, Shiyan Li, Yumeng Huang, Tianzhe Chen, Youjun Ding, Qian Tan","doi":"10.1038/s41419-025-07494-3","DOIUrl":"10.1038/s41419-025-07494-3","url":null,"abstract":"<p><p>N⁶-methyladenosine (m⁶A) RNA modification impaired autophagy results in delayed diabetic wound healing. In this study, it was found that fat mass and obesity-associated protein (FTO) was significantly downregulated in the epidermis of diabetic patients, STZ-induced mice and db/db mice (type I and II diabetic mice) with prolonged hyperglycemia, as well as in different types of keratinocyte cell lines treated with short-term high glucose medium. The knockout of FTO affected the biological functions of keratinocytes, including enhanced apoptosis, inhibited autophagy, and delayed wound healing, producing consistent results with high-glucose medium treatment. High-throughput analysis revealed that tribbles pseudokinase 3 (TRIB3) served as the downstream target gene of FTO. In addition, both in vitro and in vivo experiments, TRIB3 overexpression partially rescued biological functions caused by FTO-depletion, promoting keratinocyte migration and proliferation via autophagy. Epigenetically, FTO modulated m⁶A modification in the 3'UTR of TRIB3 mRNA and enhanced TRIB3 stability in a YTHDF2-dependent manner. Collectively, this study identifies FTO as an accelerator of diabetic wound healing and modulates autophagy via regulating TRIB3 in keratinocytes, thereby benefiting the development of a m⁶A-targeted therapy for refractory diabetic wounds.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"222"},"PeriodicalIF":8.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncogenic activation of SMYD3-SHCBP1 promotes breast cancer development and is coupled with resistance to immune therapy.","authors":"Lihua Mo, Min Deng, Ragini Adhav, Yuni Chan, Josh Haipeng Lei, Sek Man Su, Xin Zhang, Tingting An, Jianlin Liu, Jianjie Li, Xiaodong Shu, Jun Xu, Yuqing Wang, Lin Chen, Yan-Gao Man, Ning-Yi Shao, Tingxiu Xiang, Chu-Xia Deng, Xiaoling Xu","doi":"10.1038/s41419-025-07570-8","DOIUrl":"10.1038/s41419-025-07570-8","url":null,"abstract":"<p><p>Breast cancer initiation and progression are driven by various oncogenic factors and their effects on the surrounding microenvironments. Through integrative analysis of ChIP-sequencing and RNA-sequencing with fast proliferating mammary epithelial cells from pregnant Brca1^MKO and wild type (WT) mice, we found that elevated Smyd3-Shcbp1 signaling is featured with activation of the Ras-MAPK pathway and increased transcription activity in both premalignant mammary epithelium and tumor cells. Smyd3-Shcbp1 signaling shapes the tumor immunosuppressive microenvironment (TIME) and is associated with immune therapy resistance to PD1 antibody treatment. Trametinib, a potent inhibitor of MEK/MAPK, could reverse the expression of Smyd3 and Shcbp1 in both Brca1 mutant and WT tumor bearing mice. We further demonstrated that the combinatory treatment of trametinib together with PD1 antibody enhances the function of effector T cells, sensitizing tumors with elevated Smyd3 and Shcbp1 signaling to αPD1 treatment. This study advances the understanding of breast tumor progression and provides a new selective strategy for breast cancer patients.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"220"},"PeriodicalIF":8.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel clinically relevant antagonistic interplay between prolactin and oncogenic YAP-CCN2 pathways as a differentiation therapeutic target in breast cancer.","authors":"Xueqing Liu, Alaa Moamer, Roger Gomes da Silva, Aidan Shoham-Amizlev, Dana Hamam, Anwar Shams, Jean-Jacques Lebrun, Suhad Ali","doi":"10.1038/s41419-025-07547-7","DOIUrl":"10.1038/s41419-025-07547-7","url":null,"abstract":"<p><p>Cellular differentiation limits cellular plasticity allowing cells to attain their specialized functional characteristics and phenotypes, whereas loss of differentiation is a hallmark of cancer. Thus, characterizing mechanisms underlying differentiation is key to discover new cancer therapeutics. We report a novel functional antagonistic relationship between the prolactin (PRL)/prolactin receptor (PRLR) differentiation pathway and YAP-CCN2 oncogenic pathway in normal mammary epithelial cells and breast cancer cells that is essential for establishing/maintaining acinar morphogenesis, cell-cell junctions and the intracellular localization of apical-basal polarity protein complexes (Par, Crumb and Scrib). Importantly, using CRISPR knockout of the PRLR in MCF7, HR+ breast cancer cells, further revealed that the negative relationship between PRL/PRLR pathway and YAP-CCN2 pathway is critical in suppressing luminal-to-basal stem-like lineage plasticity. Furthermore, the clinical relevance of this interplay was evaluated using bioinformatics approaches on several human datasets, including samples from normal breast epithelium, breast cancer, and 33 other cancer types. This analysis revealed a positive correlation between PRLR and the YAP suppressor Hippo pathway and a co-expression gene network driving favourable patients' survival outcomes in breast cancer. The therapeutic potential of this interplay was also evaluated in vitro using MDA-MB-231 cells, a preclinical model of human triple-negative breast cancer, where treatment with PRL and Verteporfin, an FDA-approved pharmacological YAP-inhibitor, alone or their combination suppressed the expression of the mesenchymal marker vimentin and the stem cell marker CD44 as well as reduced their Ki67 proliferative marker expression. Collectively, our results emphasize the pro-differentiation role of PRL/PRLR pathway in mammary and breast cancer cells and highlight that promoting PRL/PRLR signaling while inhibiting the YAP-CCN2 oncogenic pathway can be exploited as a differentiation-based combination therapeutic strategy in breast cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"221"},"PeriodicalIF":8.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSF3R-AS promotes hepatocellular carcinoma progression and sorafenib resistance through the CSF3R/JAK2/STAT3 positive feedback loop.","authors":"Ziyang Feng, Yan Gao, Changjing Cai, Jun Tan, Ping Liu, Yihong Chen, Gongping Deng, Yanhong Ouyang, Xuewen Liu, Ke Cao, Shan Zeng, Ying Han, Xiangying Deng, Hong Shen","doi":"10.1038/s41419-025-07558-4","DOIUrl":"https://doi.org/10.1038/s41419-025-07558-4","url":null,"abstract":"<p><p>Antisense circular RNA is a special type of circular RNA that is derived from the antisense complementary strand of parental mRNA. However, the function of antisense circRNA in hepatocellular carcinoma (HCC) is still unclear. Here, we reported that CSF3R-AS was upregulated in HCC and correlated with a poor prognosis. CSF3R-AS promoted the proliferation, angiogenesis, and metastasis of HCC, and inhibited apoptosis. Mechanistically, CSF3R-AS has a 180-base complementary pairing sequence with its parental mRNA CSF3R, which can directly bind to CSF3R and recruit RBMS3 to stabilize its parental mRNA, and finally activate JAK2/STAT3 signaling pathway. Interestingly, STAT3 can act as a transcription factor of CSF3R-AS, which means that there is a CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop in HCC. Finally, the CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop was also activated in HCC sorafenib-resistant cells, and blocking this loop was expected to improve the sensitivity of HCC to sorafenib. These findings suggested that the CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop could promote HCC progression and sorafenib resistance. Blocking this loop is expected to provide new research directions and therapy targets for HCC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"217"},"PeriodicalIF":8.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11953311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Absence of CDK12 in oocyte leads to female infertility.","authors":"Denisa Jansova, Veronika Sedmikova, Fatima J Berro, Daria Aleshkina, Michal Dvoran, Michal Kubelka, Jitka Rezacova, Jana Rutarova, Jiri Kohoutek, Andrej Susor","doi":"10.1038/s41419-025-07536-w","DOIUrl":"10.1038/s41419-025-07536-w","url":null,"abstract":"<p><p>Transcriptional activity and gene expression are critical for the development of mature, meiotically competent oocytes. Our study demonstrates that the absence of cyclin-dependent kinase 12 (CDK12) in oocytes leads to complete female sterility, as fully developed oocytes capable of completing meiosis I are absent from the ovaries. Mechanistically, CDK12 regulates RNA polymerase II activity in growing oocytes and ensures the maintenance of the physiological maternal transcriptome, which is essential for protein synthesis that drives further oocyte growth. Notably, CDK12-deficient growing oocytes exhibit a 71% reduction in transcriptional activity. Furthermore, impaired oocyte development disrupts folliculogenesis, leading to premature ovarian failure without terminal follicle maturation or ovulation. In conclusion, our findings identify CDK12 as a key master regulator of the oocyte transcriptional program and gene expression, indispensable for oocyte growth and female fertility. A schematic illustrating the effects of loss of CDK12 in mammalian oocytes on the regulation of transcription by polymerase II and the concomitant effects on translation. This disruption leads to an aberrant transcriptome and translatome, resulting in the absence of fully mature oocytes and ultimately female sterility.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"213"},"PeriodicalIF":8.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}