Molecular Cell最新文献_第3页

A feedback mechanism of m6A via PARP1-mediated ADP ribosylation of METTL3/METTL14 通过parp1介导的METTL3/METTL14的ADP核糖化，m6A的反馈机制

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-13 DOI: 10.1016/j.molcel.2026.09.027

Yongtai Bai,Zhe Zhou,Xueqing Yan,Xin Li,Yuyang Dong,Tingyang Zhou,Ye Xiao,Manfei Si,Qiang Liu,Jingying Peng,Chengqi Yi

引用次数: 0

Transposable element splicing reveals a tumor-enriched class of gene-independent transcripts 转座元件剪接揭示了一类肿瘤富集的基因独立转录本

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-13 DOI: 10.1016/j.molcel.2026.09.015

Ziteng Li,Yichao Bao,Hongwu Yu,Qin Li,Hena Zhang,Yifan Wen,Yu Yang,Yaoming Su,Jingjing Zhao,Peng Lin,Qin Ding,Yan Li,Zhixiang Hu,Xichun Hu,Xiaodong Zhu,Shenglin Huang

{"title":"Transposable element splicing reveals a tumor-enriched class of gene-independent transcripts","authors":"Ziteng Li,Yichao Bao,Hongwu Yu,Qin Li,Hena Zhang,Yifan Wen,Yu Yang,Yaoming Su,Jingjing Zhao,Peng Lin,Qin Ding,Yan Li,Zhixiang Hu,Xichun Hu,Xiaodong Zhu,Shenglin Huang","doi":"10.1016/j.molcel.2026.09.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.015","url":null,"abstract":"Transposable elements (TEs) are broadly reactivated in tumors, but their repetitive nature has limited transcript-level characterization. Here, we systematically investigate the TE-derived splicing landscape across pan-cancer samples and define a splice-resolved subset of TE-derived transcripts, termed TEtrans, with tumor enrichment and gene independence. TEtrans initiate within TEs, spliced within or between TE loci, and are composed predominantly of TE sequences. Their expression was associated with stemness and inflammation regulators in a context-dependent manner. Functional analyses identify an endogenous retrovirus-derived TEtrans that promotes colorectal cancer growth by enhancing topoisomerase I-mediated DNA relaxation. A subset of TEtrans encodes shared tumor antigens that elicit antigen-specific cytotoxic T cell responses, while a murine TEtrans-like transcript mediates antigen-dependent tumor control in vivo. Collectively, TEtrans represent a splice-resolved source of TE-derived oncogenic drivers and actionable tumor antigens, broadening the scope of TE reactivation in cancer.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152669","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}

引用次数: 0

PHYHD1-mediated translational control regulates renal cell carcinoma progression phyhd1介导的翻译控制调控肾细胞癌的进展

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-12 DOI: 10.1016/j.molcel.2026.09.020

Qian Liang,Giada Zurlo,Junru Jin,Dengfeng Huang,Yudong Wei,Shuangjie Shen,Chengheng Liao,Tao Wang,Cheng Zhang,Jin Zhou,Hongyi Liu,Jun Fang,Haoyong Fu,Masashi Takeda,Xiang Li,Xiang David Li,Jian Zhou,Jinfan Wang,Tao Yue,James Brugarolas,Michael Buszczak,Qing Zhang

{"title":"PHYHD1-mediated translational control regulates renal cell carcinoma progression","authors":"Qian Liang,Giada Zurlo,Junru Jin,Dengfeng Huang,Yudong Wei,Shuangjie Shen,Chengheng Liao,Tao Wang,Cheng Zhang,Jin Zhou,Hongyi Liu,Jun Fang,Haoyong Fu,Masashi Takeda,Xiang Li,Xiang David Li,Jian Zhou,Jinfan Wang,Tao Yue,James Brugarolas,Michael Buszczak,Qing Zhang","doi":"10.1016/j.molcel.2026.09.020","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.020","url":null,"abstract":"The mechanisms underlying renal cell carcinoma (RCC) progression remain incompletely understood. Here, we identify phytanoyl-CoA dioxygenase domain containing 1 (PHYHD1) as a tumor suppressor that regulates translational homeostasis and RCC progression. Progressive PHYHD1 loss promotes tumor advancement and predicts poor prognosis, as revealed by integrative deep learning analysis of pan-cancer datasets. Restoring PHYHD1 suppresses tumor growth in RCC cell and patient-derived xenograft (PDX) models independently of its dioxygenase activity. Mechanistically, PHYHD1 interacts with translation elongation factor eEF1A1, alters its association with ribosomes, and restrains protein translation. Ribosome profiling and RNA-seq identify ceramide transporter 1 (CERT1) as a key effector of the PHYHD1-eEF1A1 axis. PHYHD1 depletion enhances CERT1 translation, whereas targeting CERT1 impairs proliferation of PHYHD1-deficient cells. These findings define a PHYHD1-eEF1A1-CERT1 axis that controls translation during RCC progression and highlight CERT1 as a potential therapeutic target in PHYHD1-deficient tumors.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"88 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151819","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}

引用次数: 0

A CK2-β-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability CK2-β-TrCP激酶- e3泛素连接酶级联是调节色氨酸2,3-双加氧酶稳定性的代谢传感器

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-12 DOI: 10.1016/j.molcel.2026.09.023

Alina S. Thielen,Bastian Bräuning,Karthik V. Gottemukkala,Judith Müller,J. Rajan Prabu,Pooja Verma,Simon Klaessens,Benoit J. Van den Eynde,Gary Kleiger,Peter J. Murray,Brenda A. Schulman

{"title":"A CK2-β-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability","authors":"Alina S. Thielen,Bastian Bräuning,Karthik V. Gottemukkala,Judith Müller,J. Rajan Prabu,Pooja Verma,Simon Klaessens,Benoit J. Van den Eynde,Gary Kleiger,Peter J. Murray,Brenda A. Schulman","doi":"10.1016/j.molcel.2026.09.023","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.023","url":null,"abstract":"Small molecules toggling the ubiquitin-proteasome system (UPS) are powerful regulators of protein degradation, yet how endogenous ligands gate UPS decisions remains poorly understood. Here, we define control of UPS access to human tryptophan 2,3-dioxygenase (TDO2), which converts the amino acid tryptophan (Trp) to N-formylkynurenine. When Trp concentrations are limiting, TDO2 is degraded to avert hypotryptophanemia. We discovered that a CK2-β-TrCP kinase-E3 ligase cascade generates and recognizes phosphodegrons in TDO2 unless they are shielded by Trp binding at an exosite distal from the catalytic site. Effects of Trp analogs on CK2-β-TrCP-dependent ubiquitylation indicated that the indole, amino, and carboxylate groups collectively protect TDO2. Cryo-EM reveals that these moieties organize a Trp-ordered flap that covers the exosite and thereby restricts generation of adjacent phosphodegrons. In the absence of Trp, the flap is flexible, enabling phosphorylation-coupled ubiquitylation. Overall, our data uncovered an endogenous small molecule conformationally stabilizing its own metabolizing enzyme through protection from a phosphorylation-ubiquitylation cascade.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"238 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151858","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}

引用次数: 0

Oligo(uridine) tailing and exonucleolytic decay drive 40S ribosome degradation in response to stress. 寡核苷酸（尿苷）尾化和外切核衰变驱动40S核糖体对应激的降解。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-09 DOI: 10.1016/j.molcel.2026.09.021

Frances F Diehl, Allen R Buskirk, Rachel Green

引用次数: 0

40S ribosome remodeling triggers 18S rRNA U-tailing and DIS3L2-dependent decay. 40S核糖体重塑触发18S rRNA u尾化和dis3l2依赖性衰变。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-09 DOI: 10.1016/j.molcel.2026.09.022

Akruti Shah, Aaztli R Coria, Jennifer T Miller, Emilien Orgebin, Wilfried Guiblet, Acong Yang, Shuo Gu, Colin Chih-Chien Wu

{"title":"40S ribosome remodeling triggers 18S rRNA U-tailing and DIS3L2-dependent decay.","authors":"Akruti Shah, Aaztli R Coria, Jennifer T Miller, Emilien Orgebin, Wilfried Guiblet, Acong Yang, Shuo Gu, Colin Chih-Chien Wu","doi":"10.1016/j.molcel.2026.09.022","DOIUrl":"10.1016/j.molcel.2026.09.022","url":null,"abstract":"<p><p>Eliminating defective ribosomes through quality control is essential for accurate protein synthesis. However, the mechanisms that commit defective ribosomal subunits to decay remain poorly defined. Here, we identify a tandem mechanism in which ubiquitin-dependent ribosome remodeling and 18S rRNA uridylation lead to 40S ribosomal subunit decay. Specifically, we use an in vitro reconstitution system to show that the atypical kinase RIOK3 remodels 40S ribosomal subunits, thereby exposing the 3' end of 18S rRNA. Nanopore direct RNA sequencing reveals that this remodeling event promotes oligo-uridylation, generating uridylated 18S rRNA decay intermediates. Uridylated 18S rRNA is further degraded by the 3'-5' exoribonuclease DIS3L2. Moreover, DIS3L2-mediated exoribonucleolytic cleavage triggers endoribonucleolytic decay of the 18S rRNA, amplifying turnover. Together, our findings define a stepwise mechanism in which ribosome remodeling and RNA tailing commit defective 40S subunits to elimination, establishing a mechanistic framework for ribosome surveillance in mammalian cells.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148332","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}

引用次数: 0

Mechanistic insights into chromatin modulation by the “orphan” remodeler ATRX “孤儿”重塑剂ATRX对染色质调节的机制见解

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-08 DOI: 10.1016/j.molcel.2026.09.013

Suling Duan,Tsz-Fung Wong,Xian Yang,Haocheng Yang,Huimin Xi,Yanxiang Zhao,Zhong-Ping Yao,Yuanliang Zhai,Jianyou Liao,Jason W.H. Wong,Tao Ni,Keda Zhou,Yang Liu

{"title":"Mechanistic insights into chromatin modulation by the “orphan” remodeler ATRX","authors":"Suling Duan,Tsz-Fung Wong,Xian Yang,Haocheng Yang,Huimin Xi,Yanxiang Zhao,Zhong-Ping Yao,Yuanliang Zhai,Jianyou Liao,Jason W.H. Wong,Tao Ni,Keda Zhou,Yang Liu","doi":"10.1016/j.molcel.2026.09.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.013","url":null,"abstract":"Alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX) is an ATP-dependent chromatin remodeler that performs diverse functions. The mechanism by which ATRX modulates chromatin is unknown. Here, our cryo-electron microscopy (cryo-EM) structure revealed that human ATRX recognizes the nucleosome through its C-terminal regions by embracing and unwrapping ∼18 base pair nucleosomal DNA near entry/exit sites in the presence of ADP⋅BeF3. Strikingly, the DNA minor groove between super helical location (SHL)6 and SHL7 is profoundly deformed by a “pin-like” structure on the “poking helix” in ATRX, which intercalates the aromatic side chain of a phenylalanine into the base stacking. To translocate the DNA on the nucleosome, ATRX further utilizes a disordered insertion to contact the histone surface and a positively charged loop to bridge cross-gyre interactions. Both the “pin-like” structure and the histone-contacting region of ATRX were found to be essential for protecting cells from G-quadruplex DNA-induced stress, highlighting the importance of these features in ATRX-mediated chromatin remodeling.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"32 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124068","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}

引用次数: 0

Toward interpretable foundation models for molecular biology 迈向可解释的分子生物学基础模型

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-07 DOI: 10.1016/j.molcel.2026.09.030

Mukund Varma,Trey Ideker

引用次数: 0

Ribosome remodeling drives translation adaptation during viral infection and cellular stress 核糖体重塑驱动翻译适应在病毒感染和细胞应激

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-07 DOI: 10.1016/j.molcel.2026.09.008

Hsin-Yu Tsai,Luochen Liu,Rebecca H. Fleming,Julian Mintseris,Derrick Ekanayake,Jing A. Guo,Xin Gu,Steven P. Gygi,Amy S.Y. Lee

{"title":"Ribosome remodeling drives translation adaptation during viral infection and cellular stress","authors":"Hsin-Yu Tsai,Luochen Liu,Rebecca H. Fleming,Julian Mintseris,Derrick Ekanayake,Jing A. Guo,Xin Gu,Steven P. Gygi,Amy S.Y. Lee","doi":"10.1016/j.molcel.2026.09.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.008","url":null,"abstract":"The ribosome is the highly conserved molecular machine that decodes mRNAs during protein synthesis. Here, we discover that, while traditionally thought to consist of a uniform set of proteins, ribosome composition is reprogrammed to adapt to intrinsic and external cellular perturbations. During infection of human cells by non-segmented negative-sense viruses, viral entry into cells recruits the large ribosomal subunit protein rpL40 to a non-canonical site on the small subunit of 80S ribosomes near the mRNA entry site. These specialized ribosomes preferentially bind viral mRNAs to drive enhanced viral protein synthesis that is critical for replication under host pressures. Unexpectedly, we find that viruses have co-opted this translation pathway from a previously unrecognized endogenous ribosome remodeling program in which metabolic stress alters ribosome structure to promote mRNA translation required for cell survival. Thus, ribosome remodeling is a conserved mechanism that enables dynamic protein synthesis across pathogen and cellular adaptation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"20 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090105","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}

引用次数: 0

DND1-NANOS3 shapes the PGC transcriptome via a heptanucleotide sequence in mRNA 3′ UTRs DND1-NANOS3通过mRNA 3 ' utr中的七核苷酸序列塑造PGC转录组

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-01 DOI: 10.1016/j.molcel.2026.09.010

Masataka Suzawa,Chen Qiu,Ahsan H. Polash,Misaki Yamaji,Alexis A. Jacob,Wataru Horikawa,Eva M. Farroha,Murchana Barua,Xuesong Feng,Chengyu Liu,Jason G. Williams,Davide Randazzo,Vittorio Sartorelli,Eugene Valkov,Masashi Yamaji,Traci M. Tanaka Hall,Markus Hafner

引用次数: 0