Pub Date : 2026-03-24DOI: 10.1016/j.molcel.2026.02.025
Tal Fisher, Orel Mizrahi, Julie Tai-Schmiedel, Aharon Nachshon, Michal Schwartz, Meidva Patrick, Avraham Gluck, Einav Aharon, Sharon Karniely, Noam Stern-Ginossar
During infection with human cytomegalovirus (HCMV), the viral long non-coding RNA RNA2.7 becomes the most abundant polyadenylated transcript in the cell, yet its function has remained enigmatic. By combining RNA sequencing, metabolic labeling of newly synthesized RNA, and ribosome profiling, we define how RNA2.7 modulates host gene expression and promotes viral propagation. We show that RNA2.7 stabilizes numerous host mRNAs by sequestering a broad array of RNA-binding proteins, reshaping the cellular transcriptome. Accordingly, RNA2.7 is essential for HCMV-induced cell-cycle arrest at the G1-S transition specifically when infection occurs in G1, thereby enhancing viral replication in actively cycling cells. Notably, RNA2.7 expression alone is sufficient to block cell-cycle progression, and screening RNA2.7 fragments identifies a region containing an extended polyadenosine stretch that is required for this activity. Our findings reveal how RNA2.7 promotes viral replication by modulating host mRNA stability and enforcing cell-cycle arrest, creating favorable conditions for infection.
{"title":"A cytomegalovirus-encoded lncRNA blocks cell-cycle progression.","authors":"Tal Fisher, Orel Mizrahi, Julie Tai-Schmiedel, Aharon Nachshon, Michal Schwartz, Meidva Patrick, Avraham Gluck, Einav Aharon, Sharon Karniely, Noam Stern-Ginossar","doi":"10.1016/j.molcel.2026.02.025","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.02.025","url":null,"abstract":"<p><p>During infection with human cytomegalovirus (HCMV), the viral long non-coding RNA RNA2.7 becomes the most abundant polyadenylated transcript in the cell, yet its function has remained enigmatic. By combining RNA sequencing, metabolic labeling of newly synthesized RNA, and ribosome profiling, we define how RNA2.7 modulates host gene expression and promotes viral propagation. We show that RNA2.7 stabilizes numerous host mRNAs by sequestering a broad array of RNA-binding proteins, reshaping the cellular transcriptome. Accordingly, RNA2.7 is essential for HCMV-induced cell-cycle arrest at the G1-S transition specifically when infection occurs in G1, thereby enhancing viral replication in actively cycling cells. Notably, RNA2.7 expression alone is sufficient to block cell-cycle progression, and screening RNA2.7 fragments identifies a region containing an extended polyadenosine stretch that is required for this activity. Our findings reveal how RNA2.7 promotes viral replication by modulating host mRNA stability and enforcing cell-cycle arrest, creating favorable conditions for infection.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513753","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}
Pub Date : 2026-03-23DOI: 10.1016/j.molcel.2026.02.024
Shubo Zhao, Chloe S. Palma-Chaundler, Carla M. Engel, Jacqueline Cordes, Daniel Nixdorf, Michael Y. Luo, Selay Kaya, Aldwin Suryo Rahmanto, Diana van den Heuvel, Timur Mackens-Kiani, Pedro Weickert, Simon Lam, Vipul Gupta, Julia Philippou-Massier, Ivan Bagarić, Jonathan Bohlen, Graeme Hewitt, Martijn S. Luijsterburg, Roland Beckmann, Petra Beli, Julian Stingele
Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.
{"title":"RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response","authors":"Shubo Zhao, Chloe S. Palma-Chaundler, Carla M. Engel, Jacqueline Cordes, Daniel Nixdorf, Michael Y. Luo, Selay Kaya, Aldwin Suryo Rahmanto, Diana van den Heuvel, Timur Mackens-Kiani, Pedro Weickert, Simon Lam, Vipul Gupta, Julia Philippou-Massier, Ivan Bagarić, Jonathan Bohlen, Graeme Hewitt, Martijn S. Luijsterburg, Roland Beckmann, Petra Beli, Julian Stingele","doi":"10.1016/j.molcel.2026.02.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.02.024","url":null,"abstract":"Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"17 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496063","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}
Pub Date : 2026-03-23DOI: 10.1016/j.molcel.2026.02.022
Jaime Santos, Manuel Günnigmann, Radoslaw J. Gora, Marija Iljina, Masa Predin, Ilgin Eser Kotan, Pratiman De, Dhawal Choudhary, Juwon Jang, Frank Tippmann, Christopher Hins, Nenad Ban, Sander J. Tans, Shu-ou Shan, Günter Kramer, Bernd Bukau
The nascent polypeptide-associated complex (NAC) coordinates enzymatic modifications and membrane targeting of nascent chains during translation. While the role of NAC as a dynamic hub for other factors is well established, its direct role in co-translational folding is unclear. By proteome-wide profiling of co-translational NAC interactions in human cells, we found that NAC recognizes emerging segments enriched in hydrophobicity and α-helical propensity within folded domains of cytonuclear proteins. Single-molecule and structural analyses reveal that NAC, via its β-barrel domain, dynamically interacts with nascent chains at the ribosomal tunnel exit and is capable of promoting on-pathway folding. Compartment-specific nascent chain interactions of NAC further elucidate its role in targeting to the endoplasmic reticulum and in mitochondrial membrane protein biogenesis. Together, these findings show that human NAC acts as a bona fide co-translational chaperone that directly promotes early protein folding at the ribosomal tunnel exit, expanding its functional repertoire in protein biogenesis.
{"title":"NAC promotes co-translational protein folding at the ribosomal tunnel exit","authors":"Jaime Santos, Manuel Günnigmann, Radoslaw J. Gora, Marija Iljina, Masa Predin, Ilgin Eser Kotan, Pratiman De, Dhawal Choudhary, Juwon Jang, Frank Tippmann, Christopher Hins, Nenad Ban, Sander J. Tans, Shu-ou Shan, Günter Kramer, Bernd Bukau","doi":"10.1016/j.molcel.2026.02.022","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.02.022","url":null,"abstract":"The nascent polypeptide-associated complex (NAC) coordinates enzymatic modifications and membrane targeting of nascent chains during translation. While the role of NAC as a dynamic hub for other factors is well established, its direct role in co-translational folding is unclear. By proteome-wide profiling of co-translational NAC interactions in human cells, we found that NAC recognizes emerging segments enriched in hydrophobicity and α-helical propensity within folded domains of cytonuclear proteins. Single-molecule and structural analyses reveal that NAC, via its β-barrel domain, dynamically interacts with nascent chains at the ribosomal tunnel exit and is capable of promoting on-pathway folding. Compartment-specific nascent chain interactions of NAC further elucidate its role in targeting to the endoplasmic reticulum and in mitochondrial membrane protein biogenesis. Together, these findings show that human NAC acts as a bona fide co-translational chaperone that directly promotes early protein folding at the ribosomal tunnel exit, expanding its functional repertoire in protein biogenesis.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"14 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496061","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}
Pub Date : 2026-03-20DOI: 10.1016/j.molcel.2026.02.018
Lucia Falbo, Vincenzo Costanzo
Replicative single-stranded DNA gaps are emerging as central intermediates in the cellular response to replication stress. Replication frequently continues past lesions or difficult-to-replicate regions through leading-strand repriming or delayed Okazaki fragment (OKF) maturation, generating structured gaps requiring stabilization and repair. Here, we describe the major routes of gap formation, including polymerase-helicase uncoupling, impaired OKF processing, PrimPol-mediated lesion bypass, and endogenous abasic site accumulation from base excision repair and DNA methylation turnover. We examine the mechanisms that suppress, protect, and resolve these gaps, highlighting RAD51/BRCA2-mediated stabilization, PCNA modifications, PARP1- and CTC1-STN1-TEN1 (CST)-dependent fill-in pathways, and the balance between translesion synthesis and template switching. Finally, we discuss how persistent gaps drive fork degradation, genome instability, and innate immune activation, contributing to explaining the therapeutic vulnerabilities and resistance of cancer cells to PARP, polymerase Q (Pol θ), and ATR inhibitors. This perspective presents a unified model in which timely replicative gap recognition and resolution ensure genome stability.
{"title":"Replicative gaps in DNA damage tolerance, genome instability, and cancer therapy","authors":"Lucia Falbo, Vincenzo Costanzo","doi":"10.1016/j.molcel.2026.02.018","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.02.018","url":null,"abstract":"Replicative single-stranded DNA gaps are emerging as central intermediates in the cellular response to replication stress. Replication frequently continues past lesions or difficult-to-replicate regions through leading-strand repriming or delayed Okazaki fragment (OKF) maturation, generating structured gaps requiring stabilization and repair. Here, we describe the major routes of gap formation, including polymerase-helicase uncoupling, impaired OKF processing, PrimPol-mediated lesion bypass, and endogenous abasic site accumulation from base excision repair and DNA methylation turnover. We examine the mechanisms that suppress, protect, and resolve these gaps, highlighting RAD51/BRCA2-mediated stabilization, PCNA modifications, PARP1- and CTC1-STN1-TEN1 (CST)-dependent fill-in pathways, and the balance between translesion synthesis and template switching. Finally, we discuss how persistent gaps drive fork degradation, genome instability, and innate immune activation, contributing to explaining the therapeutic vulnerabilities and resistance of cancer cells to PARP, polymerase Q (Pol θ), and ATR inhibitors. This perspective presents a unified model in which timely replicative gap recognition and resolution ensure genome stability.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147492799","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}
Pub Date : 2026-03-19DOI: 10.1016/j.molcel.2026.02.015
Daniel R. Squair, Eilidh Rivers, Hanna Sowar, Arda Balci, Roosa Harmo, David J. Wright, Gaurav Beniwal, Mathieu Soetens, Sunil Mathur, Aidan Tollervey, Nicola T. Wood, Kuan-Chuan Pao, Callum Stanton, Adam J. Fletcher, Satpal Virdee
The detection of viral RNA inside cells triggers a diverse range of antiviral responses, including global translation inhibition, interferon secretion, and RNA sequestration. Mutations in the gene zinc-finger NFX1-type containing 1 (ZNFX1) cause severe pediatric immunodeficiencies, including chronic viral infection and autoinflammation. Here, we show that ZNFX1 is an RNA helicase with cryptic and unusual bifurcating E3 ubiquitin ligase activity. Nucleotide-dependent RNA binding stimulates ZNFX1 to generate complex ubiquitin chains via a two-component ubiquitin circuit wired in parallel, with ubiquitin flux occurring via two competing paths. One route produces K63-linked polyubiquitin that drives RNA entrapment within self-propagating ZNFX1 aggregates, and the other route produces K48-linked polyubiquitin that drives ZNFX1 turnover. RNA entrapment restricts RNA virus replication and is reversible by deubiquitination. Pathogenic ZNFX1 variants are defective for viral restriction, linking RNA entrapment to antiviral immunity in vivo.
{"title":"ZNFX1 uses two-component ubiquitin circuitry to quarantine viral RNA","authors":"Daniel R. Squair, Eilidh Rivers, Hanna Sowar, Arda Balci, Roosa Harmo, David J. Wright, Gaurav Beniwal, Mathieu Soetens, Sunil Mathur, Aidan Tollervey, Nicola T. Wood, Kuan-Chuan Pao, Callum Stanton, Adam J. Fletcher, Satpal Virdee","doi":"10.1016/j.molcel.2026.02.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.02.015","url":null,"abstract":"The detection of viral RNA inside cells triggers a diverse range of antiviral responses, including global translation inhibition, interferon secretion, and RNA sequestration. Mutations in the gene zinc-finger NFX1-type containing 1 (<em>ZNFX1</em>) cause severe pediatric immunodeficiencies, including chronic viral infection and autoinflammation. Here, we show that ZNFX1 is an RNA helicase with cryptic and unusual bifurcating E3 ubiquitin ligase activity. Nucleotide-dependent RNA binding stimulates ZNFX1 to generate complex ubiquitin chains via a two-component ubiquitin circuit wired in parallel, with ubiquitin flux occurring via two competing paths. One route produces K63-linked polyubiquitin that drives RNA entrapment within self-propagating ZNFX1 aggregates, and the other route produces K48-linked polyubiquitin that drives ZNFX1 turnover. RNA entrapment restricts RNA virus replication and is reversible by deubiquitination. Pathogenic ZNFX1 variants are defective for viral restriction, linking RNA entrapment to antiviral immunity <em>in vivo</em>.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478548","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}
Pub Date : 2026-03-19DOI: 10.1016/j.molcel.2026.02.019
Jasmine T. Plummer
In a recent issue of Science, Chao et al.1 describe TimeVault, an approach that allows researchers to reconstruct past transcriptional states even as cells continue to divide and differentiate. It provides an alternative to conventional single-cell RNA sequencing (scRNA-seq), which captures only a terminal “snapshot,” by preserving molecular history within intact cells.
{"title":"TimeVault: A molecular time machine for single cells","authors":"Jasmine T. Plummer","doi":"10.1016/j.molcel.2026.02.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.02.019","url":null,"abstract":"In a recent issue of <em>Science</em>, Chao et al.<span><span><sup>1</sup></span></span> describe TimeVault, an approach that allows researchers to reconstruct past transcriptional states even as cells continue to divide and differentiate. It provides an alternative to conventional single-cell RNA sequencing (scRNA-seq), which captures only a terminal “snapshot,” by preserving molecular history within intact cells.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"20 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478961","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}
Pub Date : 2026-03-19DOI: 10.1016/j.molcel.2026.02.014
You Jin Song, Min Kyung Shinn, Sushant Bangru, Yu Wang, Qinyu Sun, Qinyu Hao, Pankaj Chaturvedi, Susan M Freier, Pablo Perez-Pinera, Erik R Nelson, Andrew S Belmont, Mitchell Guttman, Supriya G Prasanth, Auinash Kalsotra, Rohit V Pappu, Kannanganattu V Prasanth
The alternative splicing (AS) of pre-mRNA regulates key cellular processes, and its dysregulation is linked to tumorigenesis. Hypoxia, a common feature of malignant tumors, triggers AS in thousands of genes. The mechanisms controlling hypoxia-responsive AS remain unclear. We observe that hypoxia-responsive spliced exons exhibit characteristics of inefficient splicing, and the genes encoding these transcripts are pre-positioned near nuclear speckles-the membraneless nuclear bodies that boost splicing. The speckle-enriched long noncoding RNA (lncRNA) MALAT1 (Metastasis-associated lung adenocarcinoma transcript 1), induced during hypoxia, associates with the hypoxia-responsive genes. Furthermore, MALAT1 promotes AS by modulating the interaction between the SR family of splicing factor 1 (SRSF1) and pre-mRNAs. Mechanistically, MALAT1 promotes the condensation of SRSF1, and the condensates are preferentially recognized and recruited by RNA polymerase II (RNAPII). Overall, our results demonstrate that MALAT1 dictates hypoxia-induced AS by organizing splicing factor condensates near speckles to enable the efficient RNAPII-mediated recruitment of splicing factors to pre-mRNAs.
{"title":"LncRNA-splicing factor condensates regulate hypoxia-responsive pre-mRNA processing near nuclear speckles.","authors":"You Jin Song, Min Kyung Shinn, Sushant Bangru, Yu Wang, Qinyu Sun, Qinyu Hao, Pankaj Chaturvedi, Susan M Freier, Pablo Perez-Pinera, Erik R Nelson, Andrew S Belmont, Mitchell Guttman, Supriya G Prasanth, Auinash Kalsotra, Rohit V Pappu, Kannanganattu V Prasanth","doi":"10.1016/j.molcel.2026.02.014","DOIUrl":"10.1016/j.molcel.2026.02.014","url":null,"abstract":"<p><p>The alternative splicing (AS) of pre-mRNA regulates key cellular processes, and its dysregulation is linked to tumorigenesis. Hypoxia, a common feature of malignant tumors, triggers AS in thousands of genes. The mechanisms controlling hypoxia-responsive AS remain unclear. We observe that hypoxia-responsive spliced exons exhibit characteristics of inefficient splicing, and the genes encoding these transcripts are pre-positioned near nuclear speckles-the membraneless nuclear bodies that boost splicing. The speckle-enriched long noncoding RNA (lncRNA) MALAT1 (Metastasis-associated lung adenocarcinoma transcript 1), induced during hypoxia, associates with the hypoxia-responsive genes. Furthermore, MALAT1 promotes AS by modulating the interaction between the SR family of splicing factor 1 (SRSF1) and pre-mRNAs. Mechanistically, MALAT1 promotes the condensation of SRSF1, and the condensates are preferentially recognized and recruited by RNA polymerase II (RNAPII). Overall, our results demonstrate that MALAT1 dictates hypoxia-induced AS by organizing splicing factor condensates near speckles to enable the efficient RNAPII-mediated recruitment of splicing factors to pre-mRNAs.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"86 6","pages":"1061-1080.e10"},"PeriodicalIF":16.6,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491426","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}
Pub Date : 2026-03-19DOI: 10.1016/j.molcel.2026.02.008
X X Li, Z Tao
In this issue, Yuan et al.1 identify a pathogen-inducible long noncoding enhancer RNA (lnc-eRNA), XSER1, that regulates rice resistance by promoting chromatin looping to regulate transcription of a nearby gene. This study establishes lnc-eRNA as a functional regulator in plant immunity, linking enhancer RNA, transcriptional regulation, chromatin looping, and accessibility.
{"title":"Deciphering a long noncoding enhancer RNA in rice immunity.","authors":"X X Li, Z Tao","doi":"10.1016/j.molcel.2026.02.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.02.008","url":null,"abstract":"<p><p>In this issue, Yuan et al.<sup>1</sup> identify a pathogen-inducible long noncoding enhancer RNA (lnc-eRNA), XSER1, that regulates rice resistance by promoting chromatin looping to regulate transcription of a nearby gene. This study establishes lnc-eRNA as a functional regulator in plant immunity, linking enhancer RNA, transcriptional regulation, chromatin looping, and accessibility.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"86 6","pages":"987-989"},"PeriodicalIF":16.6,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491481","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}
Pub Date : 2026-03-19Epub Date: 2026-03-03DOI: 10.1016/j.molcel.2026.02.007
Wenfeng Xiong, Zheng Ser, Radoslaw Mikolaj Sobota, Zhewang Lin
Nascent polypeptide chains emerging from the ribosome engage a range of co-translational factors at distinct phases of translation. These co-translational interactions are crucial for proper protein biogenesis and quality control pathways to maintain protein homeostasis. Hence, the systematic identification of these co-translational interactors provides insights into how distinct polypeptide fates are determined. Here, we developed nascent-chain interactor profiling (NCIP), a metabolic-labeling- and chemical-crosslinking-enabled proteomics method to identify proteins interacting with nascent polypeptide chains at a proteome-wide scale. Results from NCIP support the co-translational assembly model of multiple protein complexes and reveal TRIM25 as a co-translational E3 ubiquitin ligase. TRIM25 ubiquitinates misfolded nascent chains for quality control at the ribosome. Our results provide a generalizable framework to systematically profile co-translational interactors.
{"title":"Global profiling of nascent chain interactors reveals TRIM25 as a co-translational E3 ubiquitin ligase.","authors":"Wenfeng Xiong, Zheng Ser, Radoslaw Mikolaj Sobota, Zhewang Lin","doi":"10.1016/j.molcel.2026.02.007","DOIUrl":"10.1016/j.molcel.2026.02.007","url":null,"abstract":"<p><p>Nascent polypeptide chains emerging from the ribosome engage a range of co-translational factors at distinct phases of translation. These co-translational interactions are crucial for proper protein biogenesis and quality control pathways to maintain protein homeostasis. Hence, the systematic identification of these co-translational interactors provides insights into how distinct polypeptide fates are determined. Here, we developed nascent-chain interactor profiling (NCIP), a metabolic-labeling- and chemical-crosslinking-enabled proteomics method to identify proteins interacting with nascent polypeptide chains at a proteome-wide scale. Results from NCIP support the co-translational assembly model of multiple protein complexes and reveal TRIM25 as a co-translational E3 ubiquitin ligase. TRIM25 ubiquitinates misfolded nascent chains for quality control at the ribosome. Our results provide a generalizable framework to systematically profile co-translational interactors.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1182-1192.e11"},"PeriodicalIF":16.6,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355896","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}
Pub Date : 2026-03-19DOI: 10.1016/j.molcel.2026.02.023
Lusong Tian, Liang Liu, Yoseop Yoon, Lindsey V. Soles, Marielle Valdez, Joshua Jeong, Clinton Yu, Lan Huang, Yongsheng Shi
In eukaryotes, incompletely and aberrantly processed mRNAs as well as numerous noncoding RNAs are retained in the nucleus and often degraded, but the underlying quality-control mechanisms remain poorly defined. Here, we identify LENG8 as a conserved RNA nuclear retention and degradation factor. LENG8 is recruited to pre-mRNAs by splicing factors, including the U1 small nuclear ribonucleoprotein particle (snRNP). It associates with PCID2 and SEM1 to form the REX (repressor of export) complex, which is conserved from yeast to humans, and causes RNA nuclear retention by acting as a dominant-negative factor for the essential mRNA export factor TREX (transcription-export)-2. Loss of LENG8 results in cytoplasmic leakage of misprocessed mRNAs, including intronically polyadenylated and intron-retained mRNAs, as well as noncoding RNAs. Moreover, LENG8 promotes nuclear RNA degradation through interactions with the RNA exosome adaptor PAXT. Together, these findings uncover a conserved RNA quality-control mechanism that ensures only correctly processed RNAs are exported.
{"title":"LENG8 mediates RNA nuclear retention and degradation in eukaryotes","authors":"Lusong Tian, Liang Liu, Yoseop Yoon, Lindsey V. Soles, Marielle Valdez, Joshua Jeong, Clinton Yu, Lan Huang, Yongsheng Shi","doi":"10.1016/j.molcel.2026.02.023","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.02.023","url":null,"abstract":"In eukaryotes, incompletely and aberrantly processed mRNAs as well as numerous noncoding RNAs are retained in the nucleus and often degraded, but the underlying quality-control mechanisms remain poorly defined. Here, we identify LENG8 as a conserved RNA nuclear retention and degradation factor. LENG8 is recruited to pre-mRNAs by splicing factors, including the U1 small nuclear ribonucleoprotein particle (snRNP). It associates with PCID2 and SEM1 to form the REX (repressor of export) complex, which is conserved from yeast to humans, and causes RNA nuclear retention by acting as a dominant-negative factor for the essential mRNA export factor TREX (transcription-export)-2. Loss of LENG8 results in cytoplasmic leakage of misprocessed mRNAs, including intronically polyadenylated and intron-retained mRNAs, as well as noncoding RNAs. Moreover, LENG8 promotes nuclear RNA degradation through interactions with the RNA exosome adaptor PAXT. Together, these findings uncover a conserved RNA quality-control mechanism that ensures only correctly processed RNAs are exported.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"271 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478545","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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