Cell Death and Differentiation最新文献

{"title":"The SETDB1-PC4-UPF1 post-transcriptional machinery controls periodic degradation of CENPF mRNA and maintains mitotic progression","authors":"Qimei Pan, Peng Luo, Yuntan Qiu, Kaishun Hu, Lehang Lin, Heyun Zhang, Dong Yin, Chunmeng Shi","doi":"10.1038/s41418-025-01465-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01465-z","url":null,"abstract":"<p>Numerous genes exhibit periodic oscillations in mRNA expression, essential for orderly cell division. Mitosis-related mRNAs fluctuate cyclically from the G2 to M phase, primarily regulated by transcription factors. However, the role of post-transcriptional regulation in this process remains unclear. Here, we demonstrated a decrease in mRNA levels of centromere protein F (<i>CENPF</i>) from the early to late G2 phase. SETDB1-PC4-UPF1 serves as a crucial post-transcriptional machinery, orchestrating the periodic degradation of <i>CENPF</i> mRNA, ensuring balanced CENP expression, proper spindle assembly, and successful mitosis. In early G2, newly synthesized <i>CENPF</i> mRNAs accumulate and bind to PC4, leading to SETDB1-mediated PC4 dimethylation at K35. In late G2, dimethylated PC4 interacts with UPF1 to promote deadenylation-dependent degradation of <i>CENPF</i> mRNAs, forming a regulatory loop for CENP homeostasis. Elevated PC4 dimethylation in hepatocellular carcinoma, coupled with increased sensitivity to taxanes upon its inhibition, suggests promising therapeutic avenues. These findings suggest a post-transcriptional quality control mechanism regulating cyclic mitotic mRNA fluctuations, providing comprehensive insights into cell cycle gene regulation dynamics.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518148","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":"Metabolic reprogramming in astrocytes prevents neuronal death through a UCHL1/PFKFB3/H4K8la positive feedback loop","authors":"Junjun Xiong, Xuhui Ge, Dishui Pan, Yufeng Zhu, Yitong Zhou, Yu Gao, Haofan Wang, Xiaokun Wang, Yao Gu, Wu Ye, Honglin Teng, Xuhui Zhou, Zheng Wang, Wei Liu, Weihua Cai","doi":"10.1038/s41418-025-01467-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01467-x","url":null,"abstract":"<p>Astrocytic metabolic reprogramming is an adaptation of metabolic patterns to meet increased energy demands, although the role after spinal cord injury (SCI) remains unclear. Analysis of single-cell RNA sequencing (scRNA-seq) data identified an increase in astrocytic glycolysis, while PFKFB3, a key regulator of glycolytic flux, was significantly upregulated following SCI. Loss of PFKFB3 in astrocytes prohibited neuronal energy supply and enhanced neuronal ferroptosis in vitro and expanded infiltration of CD68⁺ macrophages/microglia, exacerbated neuronal loss, and hindered functional recovery in vivo after SCI. Mechanistically, deubiquitinase UCHL1 plays a crucial role in stabilizing and enhancing PFKFB3 expression by cleaving K48-linked ubiquitin chains. Genetic deletion of <i>Uchl1</i> inhibited locomotor recovery after SCI by suppression of PFKFB3-induced glycolytic reprogramming in astrocytes. Furthermore, the UCHL1/PFKFB3 axis increased lactate production, leading to enhanced histone lactylation and subsequent transcription of <i>Uchl1</i> and several genes related to glycolysis, suggesting a glycolysis/H4K8la/UCHL1 positive feedback loop. These findings help to clarify the role of the UCHL1/PFKFB3/H4K8la loop in modulation of astrocytic metabolic reprogramming and reveal a potential target for treatment of SCI.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518144","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":"Chromosomal 3p loss and 8q gain drive vasculogenic mimicry via HIF-2α and VE-cadherin activation in uveal melanoma","authors":"Daniel Delgado-Bellido, Antonio Chacon-Barrado, Joaquin Olmedo-Pelayo, Carmen Jordán Perez, Paula Gilabert-Prieto, Juan Díaz-Martin, Angel Garcia-Diaz, F. J. Oliver, Enrique de Álava","doi":"10.1038/s41418-025-01469-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01469-9","url":null,"abstract":"<p>Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and is where Vasculogenic Mimicry (VM) was first described. VM enables aggressive cancer cells to independently form blood networks, complicating treatment for patients exhibiting VM. Previous studies linked VE-Cadherin phosphorylation at Y658 to gene expression via Focal Adhesion Kinase (FAK), enhancing the Kaiso/β-catenin/TCF-4 complex associated with VE-Cadherin and thereby promoting VM. Recently, an allosteric HIF-2α inhibitor (Belzutifan) was FDA-approved for VHL-associated ccRCCs. In this research, we elucidate the primary causes of VM formation in UM patients with chromosome 3p loss and chromosome 8q gain, identifying VHL, BAP1, and FAK as important factors driving VM and worsening prognosis. These factors promote abnormal activation of HIF-2α and VE-Cadherin under basal hypoxic conditions, leading to VM formation. Cytoscan 750k experiments on the MUM 2B cell line reveal a loss of chromosome 3p, where the VHL, BAP1, and CTNNB1 genes are located, and a gain of chromosome 8q (FAK), whereas the MUM 2C cell line shows a gain of chromosome 3p. This provides an outstanding cross-sectional model from patient samples to established cell lines for VM studies. LC-MS experiments demonstrate that VE-Cad/ENG expression is related to FAK activity in UM cell lines. Finally, using a combination of Belzutifan (HIF-2α inhibitor) and FAK inhibitor (FAKi), we observed a significant reduction in UM xenografts. Our results lead us to propose combining Belzutifan and FAKi as a personalized treatment strategy for UM patients. This approach inhibits VM formation and counters the initial hypoxic conditions resulting from chromosome 3p loss and chromosome 8q gain in UM patients, instilling confidence in the potential of this treatment strategy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495265","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":"Collaborative orchestration of BH3-only proteins governs Bak/Bax-dependent hepatocyte apoptosis under antiapoptotic protein-deficiency in mice","authors":"Shinnosuke Kudo, Hayato Hikita, Yoshinobu Saito, Kazuhiro Murai, Takahiro Kodama, Tomohide Tatsumi, Tetsuo Takehara","doi":"10.1038/s41418-025-01458-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01458-y","url":null,"abstract":"<p>The fine-tuned balance between anti-apoptotic Bcl-2 family proteins, such as Bcl-xL and Mcl-1, and pro-apoptotic Bcl-2 family proteins, like Bak and Bax, is crucial for maintaining hepatocyte integrity. BH3-only proteins, including Bid, Bim, Puma, Noxa, Bad, Bmf, Bik and Hrk, serve as apoptosis initiators. They are activated by various stimuli, which leads to Bak/Bax activation. We previously reported that Bid and Bim contributed to hepatocyte apoptosis through Bak/Bax activation in the absence of anti-apoptotic proteins Bcl-xL and/or Mcl-1. However, the comprehensive involvement of all eight BH3-only proteins in Bak/Bax-dependent hepatocyte apoptosis remains unclear. Puma disruption suppressed hepatocyte apoptosis in hepatocyte-specific Bcl-xL or Mcl-1 knockout (Bcl-xL^ΔHep/ΔHep or Mcl-1^ΔHep/ΔHep) mice. Disruption of Bid and Bim partially prevented lethality in Mcl-1^ΔHep/+ Bcl-xL^ΔHep/ΔHep mice, although severe hepatocyte apoptosis persisted, which was suppressed by additional Puma disruption. However, hepatocyte apoptosis was still induced compared to that in Mcl-1^ΔHep/+ Bcl-xL^ΔHep/ΔHep Bax^ΔHep/ΔHep Bak^−/− mice. Triple disruption of Bid, Bim and Puma did not prevent induction of hepatocyte apoptosis in tamoxifen-induced Mcl-1^{iΔHep/iΔHep} Bcl-xL^{iΔHep/iΔHep} mice. Primary hepatocytes, isolated from Mcl-1^fl/fl Bcl-xL^fl/fl Bid^−/− Bim^−/− Puma^−/− mice and immortalized, underwent apoptosis with doxycycline-dependent Cre recombination. Among the remaining five BH3-only proteins, Bik and Hrk were not expressed in these cells, and Noxa knockdown, but not Bad or Bmf knockdown, reduced apoptosis. Noxa disruption alleviated hepatocyte apoptosis in Mcl-1^ΔHep/ΔHep mice and tamoxifen-induced Mcl-1^{iΔHep/iΔHep} Bcl-xL^{iΔHep/iΔHep} Bid^−/− Bim^−/− Puma^−/− mice, prolonging survival. Apoptosis persisted in immortalized primary hepatocytes isolated from Mcl-1^fl/fl Bcl-xL^fl/fl Bid^−/− Bim^−/− Puma^−/− Noxa^−/− mice where doxycycline-dependent Cre recombination was induced, but was completely suppressed by Bak/Bax knockdown, while Bad or Bmf knockdown had no effect. In conclusion, among the eight BH3-only proteins, Puma and Noxa, alongside Bid and Bim, contributed to Bak/Bax-dependent hepatocyte apoptosis, but not indispensably, in the absence of Mcl-1 and Bcl-xL.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"65 5 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477661","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":"Tripartite motif-containing protein 26 promotes colorectal cancer growth by inactivating p53","authors":"Zhihui Tan, Hyun Min Ko, Parnian Naji, Rong Zhu, Jieqiong Wang, Shibo Huang, Yiwei Zhang, Shelya X. Zeng, Hua Lu","doi":"10.1038/s41418-025-01463-1","DOIUrl":"https://doi.org/10.1038/s41418-025-01463-1","url":null,"abstract":"<p>Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that exhibits divergent roles in various cancer types (oncogenic and anti-oncogenic). This study investigates the interaction of TRIM26 with the tumor suppressor protein p53 in colorectal cancer (CRC) cells by performing a comprehensive set of biochemical, cell-based assays, and xenograft experiments. As a result, we found that overexpression of TRIM26 significantly enhances CRC cell proliferation and colony formation, while knockdown of TRIM26 suppresses these processes. Xenograft experiments further validated the tumor-promoting role of TRIM26 in CRC. Supporting this is that TRIM26 is highly expressed in human CRC tissues as revealed by our analysis of the TCGA database. Biochemically, TRIM26 directly bound to the C-terminus of p53 and facilitated its ubiquitination, resulting in proteolytic degradation and attenuated p53 activity independently of MDM2. Also, TRIM26 increased the MDM2-mediated ubiquitination of p53 by binding to MDM2’s C-terminus. This study uncovers the oncogenic potential of TRIM26 in CRC by inhibiting p53 function. Through its ubiquitin ligase activity, TRIM26 destabilizes p53, consequently promoting CRC cell proliferation and tumor growth. These findings shed light on the complex involvement of TRIM26 in cancer and identify this ubiquitin ligase as a potential therapeutic target for future development of CRC treatment.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"18 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477659","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":"USP38 functions as an oncoprotein by downregulating the p53 pathway through deubiquitination and stabilization of MDM2","authors":"Shanyu Zhao, Xiaoli Liu, Rongkui Luo, Zitao Jian, Chen Xu, Yingyong Hou, Xiuping Liu, Pingzhao Zhang","doi":"10.1038/s41418-025-01462-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01462-2","url":null,"abstract":"<p>Dysregulation of the MDM2-p53 pathway is a commonly observed phenomenon in cancer, where overexpression or amplification of MDM2 leads to increased degradation of p53. This results in reduced levels of p53, leading to the loss of its tumor-suppressive functions. The study focused on investigating the role of Ubiquitin-specific protease 38 (USP38) in cancer and its interaction with the MDM2-p53 axis. We revealed that USP38 positively correlates with MDM2 and negatively correlates with p53 expression. Mechanistically, USP38 directly binds to MDM2, functioning as a deubiquitinating enzyme (DUB) to stabilize MDM2 and suppress p53 expression. Knockout of USP38 hindered cancer cell proliferation, migration, and invasion, and enhanced apoptosis. Moreover, USP38 deficiency increased sensitivity to chemotherapy drugs and promoted ferroptosis in gastric and breast cancer cell lines. Importantly, these effects were found to be dependent on p53, as the downregulation of p53 reversed the phenotypic changes induced by USP38 knockout. These findings shed light on the oncogenic role of USP38 by modulating the MDM2-p53 axis, providing valuable insights into the molecular mechanisms of USP38 in cancer and potential therapeutic strategies for gastric and breast cancer.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"65 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470743","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":"CSTF2-impeded innate αβ T cell infiltration and activation exacerbate immune evasion of pancreatic cancer","authors":"Xiaowei He, Ji Liu, Yifan Zhou, Sihan Zhao, Ziming Chen, Zilan Xu, Chunling Xue, Lingxing Zeng, Shuang Liu, Shaoqiu Liu, Ruihong Bai, Shaojia Wu, Lisha Zhuang, Mei Li, Hongzhe Zhao, Quanbo Zhou, Dongxin Lin, Jian Zheng, Xudong Huang, Jialiang Zhang","doi":"10.1038/s41418-025-01464-0","DOIUrl":"https://doi.org/10.1038/s41418-025-01464-0","url":null,"abstract":"<p>Alternative cleavage and polyadenylation (APA) have gained increasing attention in cancer biology, yet its role in modulating anti-tumor immune response remains largely unexplored. Here, we identify the cleavage stimulation factor 2 (<i>CSTF2</i>), an APA-related gene, as a pivotal suppressor of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDAC). <i>CSTF2</i> promotes tumor development by inhibiting the infiltration and cytotoxic immune cell recruitment function of TCRαβ⁺CD4⁻CD8⁻NK1.1⁻ innate αβ T (iαβT) cells. Mechanistically, CSTF2 diminishes CXCL10 expression by promoting PolyA polymerase alpha (PAPα) binding to the 3’ untranslated regions of <i>CXCL10</i> RNA, resulting in shortened PolyA tails and compromised RNA stability. Furthermore, we identify Forsythoside B, a selective inhibitor targeting the RNA recognition motif of CSTF2, can effectively activate anti-tumor immunity and overcome resistance to immune checkpoint blockade (ICB) therapy. Collectively, our findings unveil CSTF2 as a promising therapeutic target for sensitizing PDAC to ICB therapy.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"65 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451885","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":"Hepatic factor MANF drives hepatocytes reprogramming by detaining cytosolic CK19 in intrahepatic cholangiocarcinoma","authors":"Qiong Mei, Yu Zhang, Hong Li, Wei Ma, Wenkai Huang, Zhengsheng Wu, Yongli Huang, Yanyan Liang, Chuansheng Wei, Jinfeng Wang, Yuefeng Ruan, Lin Yang, Yan Huang, Yujun Shen, Jun Liu, Lijie Feng, Yuxian Shen","doi":"10.1038/s41418-025-01460-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01460-4","url":null,"abstract":"<p>Intrahepatic cholangiocarcinoma (ICC) is characterized by poor prognosis and limited treatment. Hepatocytes have been considered as one of the origins of ICC, however, the underlying mechanisms remain unclear. Here, we found mesencephalic astrocyte-derived neurotrophic factor (MANF), a hepatoprotective factor, was exceptionally upregulated in human ICC tissues and experimental mouse ICC models induced by sleeping beauty transposon (SBT) or thioacetamide (TAA) challenge. We identified MANF as a biomarker for distinguishing the primary liver cancer and verified the oncogenic role of MANF in ICC using cell lines overexpressing/knocked down MANF and mice specifically knocked in/out MANF in hepatocytes. Lineage tracing revealed that MANF promoted mature hepatocyte transformation into ICC cells. Mechanistically, MANF interacted with CK19 at Ser35 to suppress CK19 membrane recruitment. Cytosolic CK19 bound to AR domain of Notch2 intracellular domain (NICD2) to stabilize NICD2 protein level and trigger Notch signaling, which contributed to hepatocyte transformation to ICC cells. We uncover a novel profile of MANF and the original mechanism, which shed light on ICC diagnosis and intervention.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"6 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443320","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":"The LINC01315-encoded small protein YAPer-ORF competes with PRP4k to hijack YAP signaling to aberrantly promote cell growth","authors":"Zhu Xie, Chao Li, Rui Huang, Bo Wu, Qian Huang, Zhe Zhang, Tongjin Zhao, Lingqian Wu, Chengtao Li, Jianfeng Shen, Hongyan Wang","doi":"10.1038/s41418-025-01449-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01449-z","url":null,"abstract":"<p>The dysregulation of YAP activity is implicated in abnormal organ size and the pathogenesis of diverse diseases, including cancer. However, the functional regulation of YAP activity by lncRNA-encoded peptides remains elusive. In this study, we report the identification of a small protein (93 aa) encoded by the lncRNA LINC01315. This small protein, termed YAPer-ORF, preferentially interacted with GNAQ/11 mutants to augment YAP activity. Mechanistically, YAPer-ORF was located in the nucleus and competed with YAP to bind the nuclear kinase PRP4K to hinder YAP phosphorylation. This decreased phosphorylation of YAP by YAPer-ORF promoted YAP retention in the nucleus and facilitated the expression of downstream target genes such as <i>CCND1</i>. In both cancerous and noncancerous models, YAPer-ORF prominently drove cell proliferation in a CCND1-dependent manner. Notably, cardiac-specific genetic knock-in of the human YAPer-ORF in mice significantly increased heart size through increased cardiomyocyte proliferation, underscoring the role of YAPer-ORF in cell proliferation. Moreover, treatment with an anti-YAPer-ORF neutralizing antibody effectively suppressed uveal melanoma growth, highlighting the therapeutic potential of targeting YAPer-ORF. These findings collectively establish YAPer-ORF as a critical regulator of YAP activity, further highlighting the disruption of YAPer-ORF activity as a potential therapeutic strategy against YAP-driven human cancers and developmental diseases.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"10 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435019","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":"Distinct developmental outcomes in DNA repair-deficient FANCC c.67delG mutant and FANCC−/− Mice","authors":"Swarna Beesetti, Cliff Guy, Shyam Sirasanagandla, Mao Yang, Rhea Jr Sumpter, Heather Sheppard, Stephane Pelletier, Marcin W. Wlodarski, Douglas R. Green","doi":"10.1038/s41418-025-01461-3","DOIUrl":"https://doi.org/10.1038/s41418-025-01461-3","url":null,"abstract":"<p>Fanconi Anemia (FA) is an autosomal recessive disorder characterized by diverse clinical manifestations such as aplastic anemia, cancer predisposition, and developmental defects including hypogonadism, microcephaly, organ dysfunction, infertility, hyperpigmentation, microphthalmia, and skeletal defects. In addition to the well-described defects in DNA repair, mitochondrial dysfunction due to defects in mitochondrial autophagy (mitophagy) is also associated with FA, although its contribution to FA phenotypes is unknown. This study focused on the FANCC gene, which, alongside other FA genes, is integral to DNA repair and mitochondrial quality control. In the present study, we created a FANCC mutant mouse model, based on a human mutation (FANCC c.67delG) that is defective in DNA repair but proficient in mitophagy. We found that the FANCC c.67delG mutant mouse model recapitulates some phenotypes observed in FA patients, such as cellular hypersensitivity to DNA cross-linking agents and hematopoietic defects. In contrast, FA phenotypes such as microphthalmia, hypogonadism, and infertility, present in FANCC-deficient mice, were absent in the FANCC c.67delG mice, suggesting that the N-terminal 55 amino acids of FANCC are dispensable for these developmental processes. Furthermore, the FANCC c.67delG mutation preserved mitophagy, and unlike the FANCC null mutation, did not lead to the accumulation of damaged mitochondria in cells or tissues. This study highlights the multifaceted nature of the FANCC protein, with distinct domains responsible for DNA repair and mitophagy. Our results suggest that developmental defects in FA may not solely stem from DNA repair deficiencies but could also involve other functions, such as mitochondrial quality control.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"64 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434996","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}