Molecular and Cellular Biology最新文献

Mutations at BCL11B Exon 4 Associated with T Cell Acute Lymphoblastic Leukemia Are Facilitated by AID and Formation of Non-B DNA Conformations. 与 T 细胞急性淋巴细胞白血病有关的 BCL11B 第 4 外显子突变由 AID 促进并形成非 B DNA 构型。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-11-07 DOI: 10.1080/10985549.2024.2419661

Urbi Roy, Anju Sharma, Shivangi Sharma, Sumedha Dahal, Nitu Kumari, Sagar Sanjiv Desai, Susmita Kumari, Jyotika Dixit, Arun Sharma M, Najma Nujoom, Bibha Choudhary, Sathees C Raghavan

{"title":"Mutations at BCL11B Exon 4 Associated with T Cell Acute Lymphoblastic Leukemia Are Facilitated by AID and Formation of Non-B DNA Conformations.","authors":"Urbi Roy, Anju Sharma, Shivangi Sharma, Sumedha Dahal, Nitu Kumari, Sagar Sanjiv Desai, Susmita Kumari, Jyotika Dixit, Arun Sharma M, Najma Nujoom, Bibha Choudhary, Sathees C Raghavan","doi":"10.1080/10985549.2024.2419661","DOIUrl":"https://doi.org/10.1080/10985549.2024.2419661","url":null,"abstract":"One of the primary reasons behind the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL) is the deregulation of the transcription factor BCL11B. The exon 4 of BCL11B harbors several driver mutations, which abolishes its DNA-binding ability. The high frequency of C > T or G > A conversion in close vicinity of AID (Activation-induced cytidine deaminase)-hotspot motifs in the deregulated gene prompted us to investigate the role of AID in BCL11B mutagenesis. Our results reveal that AID is expressed in T-ALL patient-derived cells, binds to BCL11B fragile region (FR) in exon 4 of T cells in vivo, and generates a signature mutation pattern in this region. The mutation frequency in BCL11B FR could be modulated upon overexpression of the AID gene in the knockout background, further suggesting the involvement of AID in BCL11B mutagenesis. Importantly, various lines of experimentation reveal that BCL11B FR could fold into parallel G-quadruplex, triplex, and hairpin structures, which could act as a replication/transcription block, causing mutagenesis. Thus, our results suggest that AID binds to BCL11B exon 4 due to non-B DNA formation, causing U:G mismatches or replication blocks, which, when repaired erroneously, generates deleterious mutations, resulting in loss of functionality of BCL11B, and thus becomes the cause of T-ALL.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604653","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}

引用次数: 0

Reconstitution of Rab11-FIP4 Expression Rescues Cellular Homeostasis in Cystinosis. 重建 Rab11-FIP4 表达可恢复胱氨酸沉积症的细胞稳态

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-10-22 DOI: 10.1080/10985549.2024.2410814

Farhana Rahman, Jennifer L Johnson, Mouad Ait Kbaich, Elsa Meneses-Salas, Aparna Shukla, Danni Chen, William B Kiosses, Evripidis Gavathiotis, Ana Maria Cuervo, Stephanie Cherqui, Sergio D Catz

{"title":"Reconstitution of Rab11-FIP4 Expression Rescues Cellular Homeostasis in Cystinosis.","authors":"Farhana Rahman, Jennifer L Johnson, Mouad Ait Kbaich, Elsa Meneses-Salas, Aparna Shukla, Danni Chen, William B Kiosses, Evripidis Gavathiotis, Ana Maria Cuervo, Stephanie Cherqui, Sergio D Catz","doi":"10.1080/10985549.2024.2410814","DOIUrl":"https://doi.org/10.1080/10985549.2024.2410814","url":null,"abstract":"Rab11 family interacting protein 4 (Rab11-FIP4) regulates endocytic trafficking. A possible role for Rab11-FIP4 in the regulation of lysosomal function has been proposed, but its precise function in the regulation of cellular homeostasis is unknown. By mRNA array and protein analysis, we found that Rab11-FIP4 is downregulated in the lysosomal storage disease cystinosis, which is caused by genetic defects in the lysosomal cystine transporter, cystinosin. Rescue of Rab11-FIP4 expression in Ctns-/- fibroblasts re-established normal autophagosome levels and decreased LC3B-II expression in cystinotic cells. Furthermore, Rab11-FIP4 reconstitution increased the localization of the chaperone-mediated autophagy receptor LAMP2A at the lysosomal membrane. Treatment with genistein, a phytoestrogen that upregulates macroautophagy, or the CMA activator QX77 (CA77) restored Rab11-FIP4 expression levels in cystinotic cells supporting a cross-regulation between two independent autophagic mechanisms, lysosomal function and Rab11-FIP4. Improved cellular homeostasis in cystinotic cells rescued by Rab11-FIP4 expression correlated with decreased endoplasmic reticulum stress, an effect that was potentiated by Rab11 and partially blocked by expression of a dominant negative Rab11. Restoring Rab11-FIP4 expression in cystinotic proximal tubule cells increased the localization of the endocytic receptor megalin at the plasma membrane, suggesting that Rab11-FIP4 reconstitution has the potential to improve cellular homeostasis and function in cystinosis.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470010","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}

引用次数: 0

Small Molecule Screening Identifies HSP90 as a Modifier of RNA Foci in Myotonic Dystrophy Type 1. 小分子筛选发现 HSP90 是肌营养不良症 1 型 RNA 病灶的修饰因子

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-10-17 DOI: 10.1080/10985549.2024.2408025

Sara J Johnson, Hannah L Johnson, Reid T Powell, Clifford Stephan, Fabio Stossi, Thomas A Cooper

{"title":"Small Molecule Screening Identifies HSP90 as a Modifier of RNA Foci in Myotonic Dystrophy Type 1.","authors":"Sara J Johnson, Hannah L Johnson, Reid T Powell, Clifford Stephan, Fabio Stossi, Thomas A Cooper","doi":"10.1080/10985549.2024.2408025","DOIUrl":"https://doi.org/10.1080/10985549.2024.2408025","url":null,"abstract":"Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by a CTG triplet repeat expansion within the 3' untranslated region of the DMPK gene. Expression of the expanded allele generates RNA containing long tracts of CUG repeats (CUGexp RNA) that form hairpin structures and accumulate in nuclear RNA foci; however, the factors that control DMPK expression and the formation of CUGexp RNA foci remain largely unknown. We performed an unbiased small molecule screen in an immortalized human DM1 skeletal muscle myoblast cell line and identified HSP90 as a modifier of endogenous RNA foci. Small molecule inhibition of HSP90 leads to enhancement of RNA foci and upregulation of DMPK mRNA levels. Knockdown and overexpression of HSP90 in undifferentiated DM1 myoblasts validated the impact of HSP90 with upregulation and downregulation of DMPK mRNA, respectively. Furthermore, we identified p-STAT3 as a downstream mediator of HSP90 impacting levels of DMPK mRNA and RNA foci. Interestingly, differentiated cells exhibited an opposite effect of HSP90 inhibition displaying downregulation of DMPK mRNA through a mechanism independent of p-STAT3 involvement. This study has revealed a novel mediator for DMPK mRNA and foci regulation in DM1 cells with the potential to identify targets for future therapeutic intervention.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470011","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}

引用次数: 0

The DNA Damage Repair Function of Fission Yeast CK1 Involves Targeting Arp8, a Subunit of the INO80 Chromatin Remodeling Complex. 裂殖酵母 CK1 的 DNA 损伤修复功能涉及靶向 INO80 染色质重塑复合物的一个亚基 Arp8。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-10-10 DOI: 10.1080/10985549.2024.2408016

Sierra N Cullati, Kazutoshi Akizuki, Yufan Shan, Eric Zhang, Liping Ren, Rodrigo X Guillen, Lesley A Turner, Jun-Song Chen, Jose Navarrete-Perea, Zachary C Elmore, Steven P Gygi, Kathleen L Gould

{"title":"The DNA Damage Repair Function of Fission Yeast CK1 Involves Targeting Arp8, a Subunit of the INO80 Chromatin Remodeling Complex.","authors":"Sierra N Cullati, Kazutoshi Akizuki, Yufan Shan, Eric Zhang, Liping Ren, Rodrigo X Guillen, Lesley A Turner, Jun-Song Chen, Jose Navarrete-Perea, Zachary C Elmore, Steven P Gygi, Kathleen L Gould","doi":"10.1080/10985549.2024.2408016","DOIUrl":"https://doi.org/10.1080/10985549.2024.2408016","url":null,"abstract":"The CK1 family are conserved serine/threonine kinases with numerous substrates and cellular functions. The fission yeast CK1 orthologues Hhp1 and Hhp2 were first characterized as regulators of DNA repair, but the mechanism(s) by which CK1 activity promotes DNA repair had not been investigated. Here, we found that deleting Hhp1 and Hhp2 or inhibiting CK1 catalytic activities in yeast or in human cells increased double-strand breaks (DSBs). The primary pathways to repair DSBs, homologous recombination and nonhomologous end joining, were both less efficient in cells lacking Hhp1 and Hhp2 activity. To understand how Hhp1 and Hhp2 promote DNA damage repair, we identified new substrates of these enzymes using quantitative phosphoproteomics. We confirmed that Arp8, a component of the INO80 chromatin remodeling complex, is a bona fide substrate of Hhp1 and Hhp2 important for DNA repair. Our data suggest that Hhp1 and Hhp2 facilitate DNA repair by phosphorylating multiple substrates, including Arp8.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470012","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}

引用次数: 0

Expression of Smyd1b_tv1 by Alternative Splicing in Cardiac Muscle is Critical for Sarcomere Organization in Cardiomyocytes and Heart Function. 心肌中 Smyd1b_tv1 的替代剪接表达对心肌细胞中的肌节组织和心脏功能至关重要。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-09-25 DOI: 10.1080/10985549.2024.2402660

Rui Xu, Siping Li, Chien-Ju Chien, Yongwang Zhong, Huanhuan Xiao, Shengyun Fang, Shaojun Du

{"title":"Expression of Smyd1b_tv1 by Alternative Splicing in Cardiac Muscle is Critical for Sarcomere Organization in Cardiomyocytes and Heart Function.","authors":"Rui Xu, Siping Li, Chien-Ju Chien, Yongwang Zhong, Huanhuan Xiao, Shengyun Fang, Shaojun Du","doi":"10.1080/10985549.2024.2402660","DOIUrl":"10.1080/10985549.2024.2402660","url":null,"abstract":"Smyd1, a member of the Smyd lysine methyltransferase family, plays an important role in myofibrillogenesis of skeletal and cardiac muscles. Loss of Smyd1b (a Smyd1 ortholog) function in zebrafish results in embryonic death from heart malfunction. smyd1b encodes two isoforms, Smyd1b_tv1 and Smyd1b_tv2, differing by 13 amino acids due to alternative splicing. While smyd1 alternative splicing is evolutionarily conserved, the isoform-specific expression and function of Smyd1b_tv1 and Smyd1b_tv2 remained unknown. Here we analyzed their expression and function in skeletal and cardiac muscles. Our analysis revealed expression of smyd1b_tv1 predominately in cardiac and smyd1b_tv2 in skeletal muscles. Using zebrafish models expressing only one isoform, we demonstrated that Smyd1b_tv1 is essential for cardiomyocyte differentiation and fish viability, whereas Smyd1b_tv2 is dispensable for heart development and fish survival. Cellular and biochemical analyses revealed that Smyd1b_tv1 differs from Smyd1b_tv2 in protein localization and binding with myosin chaperones. While Smyd1b_tv2 diffused in the cytosol of muscle cells, Smyd1b_tv1 was localized to M-lines and essential for sarcomere organization in cardiomyocytes. Co-IP analysis revealed a stronger binding of Smyd1b_tv1 with chaperones and cochaperones compared with Smyd1b_tv2. Collectively, these findings highlight the nonequivalence of Smyd1b isoforms in cardiomyocyte differentiation, emphasizing the critical role of Smyd1b_tv1 in cardiac function.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350048","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}

引用次数: 0

A Genome Wide CRISPR Screen Reveals That HOXA9 Promotes Enzalutamide Resistance in Prostate Cancer. 全基因组 CRISPR 筛选揭示 HOXA9 可促进前列腺癌的恩杂鲁胺抗性

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-09-20 DOI: 10.1080/10985549.2024.2401465

Michael V Roes, Frederick A Dick

{"title":"A Genome Wide CRISPR Screen Reveals That HOXA9 Promotes Enzalutamide Resistance in Prostate Cancer.","authors":"Michael V Roes, Frederick A Dick","doi":"10.1080/10985549.2024.2401465","DOIUrl":"https://doi.org/10.1080/10985549.2024.2401465","url":null,"abstract":"Androgen receptor inhibitors are commonly used for prostate cancer treatment, but acquired resistance is a significant problem. Codeletion of RB and p53 is common in castration resistant prostate cancers, however they are difficult to target pharmacologically. To comprehensively identify gene loss events that contribute to enzalutamide response, we performed a genome-wide CRISPR knockout screen in LNCaP prostate cancer cells. This revealed novel genes implicated in resistance that are largely unstudied. Gene loss events that confer enzalutamide sensitivity are enriched for GSEA categories related to stem cell and epigenetic regulation. We investigated the myeloid lineage stem cell factor HOXA9 as a candidate gene whose loss promotes sensitivity to enzalutamide. Cancer genomic data reveals that HOXA9 overexpression correlates with poor prognosis and characteristics of advanced prostate cancer. In cell culture, HOXA9 depletion sensitizes cells to enzalutamide, whereas overexpression drives enzalutamide resistance. Combination of the HOXA9 inhibitor DB818 with enzalutamide demonstrates synergy. This demonstrates the utility of our CRISPR screen data in discovering new approaches for treating enzalutamide resistant prostate cancer.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291286","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}

引用次数: 0

Midnolin, a Genetic Risk Factor for Parkinson’s Disease, Promotes Neurite Outgrowth Accompanied by Early Growth Response 1 Activation in PC12 Cells 帕金森病的遗传风险因子 Midnolin 能促进 PC12 细胞中神经元的生长，同时激活早期生长应答 1

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2024-09-12 DOI: 10.1080/10985549.2024.2399358

Ayano Chiba Chisato Kato Tadashi Nakagawa Tsukasa Osaki Kohei Nakamura Ikuo Norota Mikako Nagashima Toru Hosoi Kuniaki Ishii Yutaro Obara a Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japanb Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo Onoda, Japanc Department of Biochemistry and Molecular Biology, Yamagata University School of Medicine, Yamagata, Japan

引用次数: 0

Statement of Retraction: FLIP Protects against Hypoxia/Reoxygenation-Induced Endothelial Cell Apoptosis by Inhibiting Bax Activation. 撤回声明：FLIP通过抑制Bax活化防止缺氧/再氧诱导的内皮细胞凋亡

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-09-03 DOI: 10.1080/10985549.2024.2396764

引用次数: 0

Selective Hypoxia-Sensitive Oxomer Formation by FIH Prevents Binding of the NF-κB Inhibitor IκBβ to NF-κB Subunits FIH选择性缺氧敏感氧化物形成可阻止NF-κB抑制剂IκBβ与NF-κB亚基结合

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2024-04-22 DOI: 10.1080/10985549.2024.2338727

Yulia L. VolkovaAgnieszka E. JuchtNina OechslerRoopesh KrishnankuttyAlex von KriegsheimRoland H. WengerCarsten C. Scholza Institute of Physiology, University of Zurich, Zurich, Switzerlandb Institute of Physiology, University Medicine Greifswald, Greifswald, Germanyc Institute of Genetics and Cancer, University of Edinburgh, UK

引用次数: 0

Endogenous EWSR1 Exists in Two Visual Modalities That Reflect Its Associations with Nucleic Acids and Concentration at Sites of Active Transcription 内源性 EWSR1 存在于两种视觉模式，反映了它与核酸的关联以及在活性转录位点的浓度

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2024-03-20 DOI: 10.1080/10985549.2024.2315425

Soumya Sundara RajanVernon J. EbegboniPatricio PichlingKatelyn R. LudwigTamara L. JonesRaj ChariAndy TranMichael J. KruhlakJadranka LoncarekNatasha J. Caplena Functional Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAb Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, Maryland, USAc CCR Confocal Microscopy Core Facility, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAd Centrosome Biology Section, Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA

引用次数: 0