Pub Date : 2024-12-01Epub Date: 2024-05-08DOI: 10.1080/19491034.2024.2350178
Romane Milcamps, Thomas Michiels
Paraspeckles are non-membranous subnuclear bodies, formed through the interaction between the architectural long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) and specific RNA-binding proteins, including the three Drosophila Behavior/Human Splicing (DBHS) family members (PSPC1 (Paraspeckle Component 1), SFPQ (Splicing Factor Proline and Glutamine Rich) and NONO (Non-POU domain-containing octamer-binding protein)). Paraspeckle components were found to impact viral infections through various mechanisms, such as induction of antiviral gene expression, IRES-mediated translation, or viral mRNA polyadenylation. A complex involving NEAT1 RNA and paraspeckle proteins was also found to modulate interferon gene transcription after nuclear DNA sensing, through the activation of the cGAS-STING axis. This review aims to provide an overview on how these elements actively contribute to the dynamics of viral infections.
{"title":"Involvement of paraspeckle components in viral infections.","authors":"Romane Milcamps, Thomas Michiels","doi":"10.1080/19491034.2024.2350178","DOIUrl":"10.1080/19491034.2024.2350178","url":null,"abstract":"<p><p>Paraspeckles are non-membranous subnuclear bodies, formed through the interaction between the architectural long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) and specific RNA-binding proteins, including the three <i>Drosophila Behavior/Human Splicing</i> (DBHS) family members (PSPC1 (Paraspeckle Component 1), SFPQ (Splicing Factor Proline and Glutamine Rich) and NONO (Non-POU domain-containing octamer-binding protein)). Paraspeckle components were found to impact viral infections through various mechanisms, such as induction of antiviral gene expression, IRES-mediated translation, or viral mRNA polyadenylation. A complex involving NEAT1 RNA and paraspeckle proteins was also found to modulate interferon gene transcription after nuclear DNA sensing, through the activation of the cGAS-STING axis. This review aims to provide an overview on how these elements actively contribute to the dynamics of viral infections.</p>","PeriodicalId":74323,"journal":{"name":"Nucleus (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11086011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-03-27DOI: 10.1080/19491034.2024.2330947
Joana T Lima, Jorge G Ferreira
Cellular behavior is continuously influenced by mechanical forces. These forces span the cytoskeleton and reach the nucleus, where they trigger mechanotransduction pathways that regulate downstream biochemical events. Therefore, the nucleus has emerged as a regulator of cellular response to mechanical stimuli. Cell cycle progression is regulated by cyclin-CDK complexes. Recent studies demonstrated these biochemical pathways are influenced by mechanical signals, highlighting the interdependence of cellular mechanics and cell cycle regulation. In particular, the transition from G2 to mitosis (G2-M) shows significant changes in nuclear structure and organization, ranging from nuclear pore complex (NPC) and nuclear lamina disassembly to chromosome condensation. The remodeling of these mechanically active nuclear components indicates that mitotic entry is particularly sensitive to forces. Here, we address how mechanical forces crosstalk with the nucleus to determine the timing and efficiency of the G2-M transition. Finally, we discuss how the deregulation of nuclear mechanics has consequences for mitosis.
{"title":"Mechanobiology of the nucleus during the G2-M transition.","authors":"Joana T Lima, Jorge G Ferreira","doi":"10.1080/19491034.2024.2330947","DOIUrl":"10.1080/19491034.2024.2330947","url":null,"abstract":"<p><p>Cellular behavior is continuously influenced by mechanical forces. These forces span the cytoskeleton and reach the nucleus, where they trigger mechanotransduction pathways that regulate downstream biochemical events. Therefore, the nucleus has emerged as a regulator of cellular response to mechanical stimuli. Cell cycle progression is regulated by cyclin-CDK complexes. Recent studies demonstrated these biochemical pathways are influenced by mechanical signals, highlighting the interdependence of cellular mechanics and cell cycle regulation. In particular, the transition from G2 to mitosis (G2-M) shows significant changes in nuclear structure and organization, ranging from nuclear pore complex (NPC) and nuclear lamina disassembly to chromosome condensation. The remodeling of these mechanically active nuclear components indicates that mitotic entry is particularly sensitive to forces. Here, we address how mechanical forces crosstalk with the nucleus to determine the timing and efficiency of the G2-M transition. Finally, we discuss how the deregulation of nuclear mechanics has consequences for mitosis.</p>","PeriodicalId":74323,"journal":{"name":"Nucleus (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10978034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140295494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-05-03DOI: 10.1080/19491034.2024.2349085
Olivia Keeley, Alyssa N Coyne
The ESCRT machinery plays a pivotal role in membrane-remodeling events across multiple cellular processes including nuclear envelope repair and reformation, nuclear pore complex surveillance, endolysosomal trafficking, and neuronal pruning. Alterations in ESCRT-III functionality have been associated with neurodegenerative diseases including Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Disease (AD). In addition, mutations in specific ESCRT-III proteins have been identified in FTD/ALS. Thus, understanding how disruptions in the fundamental functions of this pathway and its individual protein components in the human central nervous system (CNS) may offer valuable insights into mechanisms underlying neurodegenerative disease pathogenesis and identification of potential therapeutic targets. In this review, we discuss ESCRT components, dynamics, and functions, with a focus on the ESCRT-III pathway. In addition, we explore the implications of altered ESCRT-III function for neurodegeneration with a primary emphasis on nuclear surveillance and endolysosomal trafficking within the CNS.
{"title":"Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease.","authors":"Olivia Keeley, Alyssa N Coyne","doi":"10.1080/19491034.2024.2349085","DOIUrl":"10.1080/19491034.2024.2349085","url":null,"abstract":"<p><p>The ESCRT machinery plays a pivotal role in membrane-remodeling events across multiple cellular processes including nuclear envelope repair and reformation, nuclear pore complex surveillance, endolysosomal trafficking, and neuronal pruning. Alterations in ESCRT-III functionality have been associated with neurodegenerative diseases including Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Disease (AD). In addition, mutations in specific ESCRT-III proteins have been identified in FTD/ALS. Thus, understanding how disruptions in the fundamental functions of this pathway and its individual protein components in the human central nervous system (CNS) may offer valuable insights into mechanisms underlying neurodegenerative disease pathogenesis and identification of potential therapeutic targets. In this review, we discuss ESCRT components, dynamics, and functions, with a focus on the ESCRT-III pathway. In addition, we explore the implications of altered ESCRT-III function for neurodegeneration with a primary emphasis on nuclear surveillance and endolysosomal trafficking within the CNS.</p>","PeriodicalId":74323,"journal":{"name":"Nucleus (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11073439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140871746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1080/19491034.2023.2202548
Jeanae M Kaneshiro, Juliana S Capitanio, Martin W Hetzer
Peripheral heterochromatin positioning depends on nuclear envelope associated proteins and repressive histone modifications. Here we show that overexpression (OE) of Lamin B1 (LmnB1) leads to the redistribution of peripheral heterochromatin into heterochromatic foci within the nucleoplasm. These changes represent a perturbation of heterochromatin binding at the nuclear periphery (NP) through a mechanism independent from altering other heterochromatin anchors or histone post-translational modifications. We further show that LmnB1 OE alters gene expression. These changes do not correlate with different levels of H3K9me3, but a significant number of the misregulated genes were likely mislocalized away from the NP upon LmnB1 OE. We also observed an enrichment of developmental processes amongst the upregulated genes. ~74% of these genes were normally repressed in our cell type, suggesting that LmnB1 OE promotes gene de-repression. This demonstrates a broader consequence of LmnB1 OE on cell fate, and highlights the importance of maintaining proper levels of LmnB1.
{"title":"Lamin B1 overexpression alters chromatin organization and gene expression.","authors":"Jeanae M Kaneshiro, Juliana S Capitanio, Martin W Hetzer","doi":"10.1080/19491034.2023.2202548","DOIUrl":"10.1080/19491034.2023.2202548","url":null,"abstract":"<p><p>Peripheral heterochromatin positioning depends on nuclear envelope associated proteins and repressive histone modifications. Here we show that overexpression (OE) of Lamin B1 (LmnB1) leads to the redistribution of peripheral heterochromatin into heterochromatic foci within the nucleoplasm. These changes represent a perturbation of heterochromatin binding at the nuclear periphery (NP) through a mechanism independent from altering other heterochromatin anchors or histone post-translational modifications. We further show that LmnB1 OE alters gene expression. These changes do not correlate with different levels of H3K9me3, but a significant number of the misregulated genes were likely mislocalized away from the NP upon LmnB1 OE. We also observed an enrichment of developmental processes amongst the upregulated genes. ~74% of these genes were normally repressed in our cell type, suggesting that LmnB1 OE promotes gene de-repression. This demonstrates a broader consequence of LmnB1 OE on cell fate, and highlights the importance of maintaining proper levels of LmnB1.</p>","PeriodicalId":74323,"journal":{"name":"Nucleus (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cb/66/KNCL_14_2202548.PMC10114975.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9569809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-10-26DOI: 10.1080/19491034.2023.2270345
Howard J Worman, Susan Michaelis
As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders. Premature aging disorders or progeroid syndromes can provide critical insights into aspects of physiological aging. A major cause of progeroid syndromes which result from mutations in the genes LMNA and ZMPSTE24 is disruption of the final posttranslational processing step in the production of the nuclear scaffold protein lamin A. LMNA encodes the lamin A precursor, prelamin A and ZMPSTE24 encodes the prelamin A processing enzyme, the zinc metalloprotease ZMPSTE24. Progeroid syndromes resulting from mutations in these genes include the clinically related disorders Hutchinson-Gilford progeria syndrome (HGPS), mandibuloacral dysplasia-type B, and restrictive dermopathy. These diseases have features that overlap with one another and with some aspects of physiological aging, including bone defects resembling osteoporosis and atherosclerosis (the latter primarily in HGPS). The progeroid syndromes have ignited keen interest in the relationship between defective prelamin A processing and its accumulation in normal physiological aging. In this review, we examine the hypothesis that diminished processing of prelamin A by ZMPSTE24 is a driver of physiological aging. We review features a new mouse (LmnaL648R/L648R) that produces solely unprocessed prelamin A and provides an ideal model for examining the effects of its accumulation during aging. We also discuss existing data on the accumulation of prelamin A or its variants in human physiological aging, which call out for further validation and more rigorous experimental approaches to determine if prelamin A contributes to normal aging.
{"title":"Prelamin A and ZMPSTE24 in premature and physiological aging.","authors":"Howard J Worman, Susan Michaelis","doi":"10.1080/19491034.2023.2270345","DOIUrl":"10.1080/19491034.2023.2270345","url":null,"abstract":"<p><p>As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders. Premature aging disorders or progeroid syndromes can provide critical insights into aspects of physiological aging. A major cause of progeroid syndromes which result from mutations in the genes <i>LMNA</i> and <i>ZMPSTE24</i> is disruption of the final posttranslational processing step in the production of the nuclear scaffold protein lamin A. <i>LMNA</i> encodes the lamin A precursor, prelamin A and <i>ZMPSTE24</i> encodes the prelamin A processing enzyme, the zinc metalloprotease ZMPSTE24. Progeroid syndromes resulting from mutations in these genes include the clinically related disorders Hutchinson-Gilford progeria syndrome (HGPS), mandibuloacral dysplasia-type B, and restrictive dermopathy. These diseases have features that overlap with one another and with some aspects of physiological aging, including bone defects resembling osteoporosis and atherosclerosis (the latter primarily in HGPS). The progeroid syndromes have ignited keen interest in the relationship between defective prelamin A processing and its accumulation in normal physiological aging. In this review, we examine the hypothesis that diminished processing of prelamin A by ZMPSTE24 is a driver of physiological aging. We review features a new mouse (<i>Lmna</i><sup>L648R/L648R</sup>) that produces solely unprocessed prelamin A and provides an ideal model for examining the effects of its accumulation during aging. We also discuss existing data on the accumulation of prelamin A or its variants in human physiological aging, which call out for further validation and more rigorous experimental approaches to determine if prelamin A contributes to normal aging.</p>","PeriodicalId":74323,"journal":{"name":"Nucleus (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10730219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54232709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-09-27DOI: 10.1080/19491034.2023.2262308
Joonyoung R Kim, Paul H Kim, Ashley Presnell, Yiping Tu, Stephen G Young
The Lmna knockout mouse (Lmna-/-) created by Sullivan and coworkers in 1999 has been widely used to examine lamin A/C function. The knockout allele contains a deletion of Lmna intron 7-exon 11 sequences and was reported to be a null allele. Later, Jahn and coworkers discovered that the mutant allele produces a 54-kDa truncated lamin A and identified, by RT-PCR, a Lmna cDNA containing exon 1-7 + exon 12 sequences. Because exon 12 encodes prelamin A's CaaX motif, the mutant lamin A is assumed to be farnesylated. In the current study, we found that the truncated lamin A in Lmna-/- mouse embryonic fibroblasts (MEFs) was predominantly nucleoplasmic rather than at the nuclear rim, leading us to hypothesize that it was not farnesylated. Our study revealed that the most abundant Lmna transcripts in Lmna-/- MEFs contain exon 1-7 but not exon 12 sequences. Exon 1-7 + exon 12 transcripts were detectable by PCR but in trace amounts. We suspect that these findings explain the nucleoplasmic distribution of the truncated lamin A in Lmna-/- MEFs, and subsequent cell transduction experiments support this suspicion. A truncated lamin A containing exon 1-7 sequence was nucleoplasmic, whereas a lamin A containing exon 1-7 + exon 12 sequences was located along the nuclear rim. Our study explains the nucleoplasmic targeting of truncated lamin A in Lmna-/- MEFs and adds to our understanding of a commonly used strain of Lmna-/- mice.
{"title":"Revisiting the truncated lamin A produced by a commonly used strain of <i>Lmna</i> knockout mice.","authors":"Joonyoung R Kim, Paul H Kim, Ashley Presnell, Yiping Tu, Stephen G Young","doi":"10.1080/19491034.2023.2262308","DOIUrl":"10.1080/19491034.2023.2262308","url":null,"abstract":"<p><p>The <i>Lmna</i> knockout mouse (<i>Lmna</i><sup>-/-</sup>) created by Sullivan and coworkers in 1999 has been widely used to examine lamin A/C function. The knockout allele contains a deletion of <i>Lmna</i> intron 7-exon 11 sequences and was reported to be a null allele. Later, Jahn and coworkers discovered that the mutant allele produces a 54-kDa truncated lamin A and identified, by RT-PCR, a <i>Lmna</i> cDNA containing exon 1-7 + exon 12 sequences. Because exon 12 encodes prelamin A's <i>CaaX</i> motif, the mutant lamin A is assumed to be farnesylated. In the current study, we found that the truncated lamin A in <i>Lmna</i><sup>-/-</sup> mouse embryonic fibroblasts (MEFs) was predominantly nucleoplasmic rather than at the nuclear rim, leading us to hypothesize that it was not farnesylated. Our study revealed that the most abundant <i>Lmna</i> transcripts in <i>Lmna</i><sup>-/-</sup> MEFs contain exon 1-7 but not exon 12 sequences. Exon 1-7 + exon 12 transcripts were detectable by PCR but in trace amounts. We suspect that these findings explain the nucleoplasmic distribution of the truncated lamin A in <i>Lmna</i><sup>-/-</sup> MEFs, and subsequent cell transduction experiments support this suspicion. A truncated lamin A containing exon 1-7 sequence was nucleoplasmic, whereas a lamin A containing exon 1-7 + exon 12 sequences was located along the nuclear rim. Our study explains the nucleoplasmic targeting of truncated lamin A in <i>Lmna</i><sup>-/-</sup> MEFs and adds to our understanding of a commonly used strain of <i>Lmna</i><sup>-/-</sup> mice.</p>","PeriodicalId":74323,"journal":{"name":"Nucleus (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bc/ad/KNCL_14_2262308.PMC10538457.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41159426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-10-31DOI: 10.1080/19491034.2023.2274655
Nuray Böğürcü-Seidel, Nadja Ritschel, Till Acker, Attila Németh
The nucleolus, the largest subcompartment of the nucleus, stands out from the nucleoplasm due to its exceptionally high local RNA and low DNA concentrations. Within this central hub of nuclear RNA metabolism, ribosome biogenesis is the most prominent ribonucleoprotein (RNP) biogenesis process, critically determining the structure and function of the nucleolus. However, recent studies have shed light on other roles of the nucleolus, exploring the interplay with various noncoding RNAs that are not directly involved in ribosome synthesis. This review focuses on this intriguing topic and summarizes the techniques to study and the latest findings on nucleolar long noncoding RNAs (lncRNAs) as well as microRNAs (miRNAs) in the context of nucleolus biology beyond ribosome biogenesis. We particularly focus on the multifaceted roles of the nucleolus and noncoding RNAs in physiology and tumor biology.
{"title":"Beyond ribosome biogenesis: noncoding nucleolar RNAs in physiology and tumor biology.","authors":"Nuray Böğürcü-Seidel, Nadja Ritschel, Till Acker, Attila Németh","doi":"10.1080/19491034.2023.2274655","DOIUrl":"10.1080/19491034.2023.2274655","url":null,"abstract":"<p><p>The nucleolus, the largest subcompartment of the nucleus, stands out from the nucleoplasm due to its exceptionally high local RNA and low DNA concentrations. Within this central hub of nuclear RNA metabolism, ribosome biogenesis is the most prominent ribonucleoprotein (RNP) biogenesis process, critically determining the structure and function of the nucleolus. However, recent studies have shed light on other roles of the nucleolus, exploring the interplay with various noncoding RNAs that are not directly involved in ribosome synthesis. This review focuses on this intriguing topic and summarizes the techniques to study and the latest findings on nucleolar long noncoding RNAs (lncRNAs) as well as microRNAs (miRNAs) in the context of nucleolus biology beyond ribosome biogenesis. We particularly focus on the multifaceted roles of the nucleolus and noncoding RNAs in physiology and tumor biology.</p>","PeriodicalId":74323,"journal":{"name":"Nucleus (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10730139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71429953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1080/19491034.2023.2178184
Katharina S Keuenhof, Verena Kohler, Filomena Broeskamp, Dimitra Panagaki, Sean D Speese, Sabrina Büttner, Johanna L Höög
The nuclear pore complex (NPC) has long been assumed to be the sole route across the nuclear envelope, and under normal homeostatic conditions it is indeed the main mechanism of nucleo-cytoplasmic transport. However, it has also been known that e.g. herpesviruses cross the nuclear envelope utilizing a pathway entitled nuclear egress or envelopment/de-envelopment. Despite this, a thread of observations suggests that mechanisms similar to viral egress may be transiently used also in healthy cells. It has since been proposed that mechanisms like nuclear envelope budding (NEB) can facilitate the transport of RNA granules, aggregated proteins, inner nuclear membrane proteins, and mis-assembled NPCs. Herein, we will summarize the known roles of NEB as a physiological and intrinsic cellular feature and highlight the many unanswered questions surrounding these intriguing nuclear events.
{"title":"Nuclear envelope budding and its cellular functions.","authors":"Katharina S Keuenhof, Verena Kohler, Filomena Broeskamp, Dimitra Panagaki, Sean D Speese, Sabrina Büttner, Johanna L Höög","doi":"10.1080/19491034.2023.2178184","DOIUrl":"10.1080/19491034.2023.2178184","url":null,"abstract":"<p><p>The nuclear pore complex (NPC) has long been assumed to be the sole route across the nuclear envelope, and under normal homeostatic conditions it is indeed the main mechanism of nucleo-cytoplasmic transport. However, it has also been known that e.g. herpesviruses cross the nuclear envelope utilizing a pathway entitled nuclear egress or envelopment/de-envelopment. Despite this, a thread of observations suggests that mechanisms similar to viral egress may be transiently used also in healthy cells. It has since been proposed that mechanisms like nuclear envelope budding (NEB) can facilitate the transport of RNA granules, aggregated proteins, inner nuclear membrane proteins, and mis-assembled NPCs. Herein, we will summarize the known roles of NEB as a physiological and intrinsic cellular feature and highlight the many unanswered questions surrounding these intriguing nuclear events.</p>","PeriodicalId":74323,"journal":{"name":"Nucleus (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9371338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Noncoding RNAs have been found to play important roles in DNA damage repair, whereas the participation of circRNA remains undisclosed. Here, we characterized ciRS-7, a circRNA containing over 70 putative miR-7-binding sites, as an enhancer of miRISC condensation and DNA repair. Both in vivo and in vitro experiments confirmed the condensation of TNRC6B and AGO2, two core protein components of human miRISC. Moreover, overexpressing ciRS-7 largely increased the condensate number of TNRC6B and AGO2 in cells, while silencing ciRS-7 reduced it. Additionally, miR-7 overexpression also promoted miRISC condensation. Consistent with the previous report that AGO2 participated in RAD51-mediated DNA damage repair, the overexpression of ciRS-7 significantly promoted irradiation-induced DNA damage repair by enhancing RAD51 recruitment. Our results uncover a new role of circRNA in liquid-liquid phase separation and provide new insight into the regulatory mechanism of ciRS-7 on miRISC function and DNA repair.
{"title":"CiRS-7 Enhances the Liquid-liquid Phase Separation of miRISC and Promotes DNA Damage Repair.","authors":"Yun-Long Wang, Li-Li Feng, Jie Shi, Wan-Ying Chen, Shu-Ying Bie, Shao-Mei Bai, Guang-Dong Zeng, Rui-Zhi Wang, Jian Zheng, Xiang-Bo Wan, Xin-Juan Fan","doi":"10.1080/19491034.2023.2293599","DOIUrl":"10.1080/19491034.2023.2293599","url":null,"abstract":"<p><p>Noncoding RNAs have been found to play important roles in DNA damage repair, whereas the participation of circRNA remains undisclosed. Here, we characterized ciRS-7, a circRNA containing over 70 putative miR-7-binding sites, as an enhancer of miRISC condensation and DNA repair. Both <i>in vivo</i> and <i>in vitro</i> experiments confirmed the condensation of TNRC6B and AGO2, two core protein components of human miRISC. Moreover, overexpressing ciRS-7 largely increased the condensate number of TNRC6B and AGO2 in cells, while silencing ciRS-7 reduced it. Additionally, miR-7 overexpression also promoted miRISC condensation. Consistent with the previous report that AGO2 participated in RAD51-mediated DNA damage repair, the overexpression of ciRS-7 significantly promoted irradiation-induced DNA damage repair by enhancing RAD51 recruitment. Our results uncover a new role of circRNA in liquid-liquid phase separation and provide new insight into the regulatory mechanism of ciRS-7 on miRISC function and DNA repair.</p>","PeriodicalId":74323,"journal":{"name":"Nucleus (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10730229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138813526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-12-05DOI: 10.1080/19491034.2023.2288476
Kamsi O Odinammadu, Khurts Shilagardi, Kelsey Tuminelli, Daniel P Judge, Leslie B Gordon, Susan Michaelis
Several related progeroid disorders are caused by defective post-translational processing of prelamin A, the precursor of the nuclear scaffold protein lamin A, encoded by LMNA. Prelamin A undergoes farnesylation and additional modifications at its C-terminus. Subsequently, the farnesylated C-terminal segment is cleaved off by the zinc metalloprotease ZMPSTE24. The premature aging disorder Hutchinson Gilford progeria syndrome (HGPS) and a related progeroid disease, mandibuloacral dysplasia (MAD-B), are caused by mutations in LMNA and ZMPSTE24, respectively, that result in failure to process the lamin A precursor and accumulate permanently farnesylated forms of prelamin A. The farnesyl transferase inhibitor (FTI) lonafarnib is known to correct the aberrant nuclear morphology of HGPS patient cells and improves lifespan in children with HGPS. Importantly, and in contrast to a previous report, we show here that FTI treatment also improves the aberrant nuclear phenotypes in MAD-B patient cells with mutations in ZMPSTE24 (P248L or L425P). As expected, lonafarnib does not correct nuclear defects for cells with lamin A processing-proficient mutations. We also examine prelamin A processing in fibroblasts from two individuals with a prevalent laminopathy mutation LMNA-R644C. Despite the proximity of residue R644 to the prelamin A cleavage site, neither R644C patient cell line shows a prelamin A processing defect, and both have normal nuclear morphology. This work clarifies the prelamin A processing status and role of FTIs in a variety of laminopathy patient cells and supports the FDA-approved indication for the FTI Zokinvy for patients with processing-deficient progeroid laminopathies, but not for patients with processing-proficient laminopathies.
几种相关的类早衰症都是由 LMNA 编码的核支架蛋白层粘连蛋白 A 的前体--前层粘连蛋白 A 翻译后加工缺陷引起的。前层蛋白 A 的 C 端会发生法尼基化和其他修饰。随后,法尼基化的 C 端片段被锌金属蛋白酶 ZMPSTE24 分解。早衰症哈钦森-吉尔福德早衰综合症(HGPS)和一种相关的类早衰症下颌骨骶骨发育不良症(MAD-B)分别是由 LMNA 和 ZMPSTE24 基因突变引起的,这两种疾病会导致无法处理层粘连蛋白 A 前体,并永久性地积聚层粘连蛋白 A 前体的法尼基化形式。据了解,法尼基转移酶抑制剂(FTI)lonafarnib能纠正HGPS患者细胞核形态的异常,并能延长HGPS患儿的寿命。重要的是,与之前的报告不同,我们在此表明,FTI治疗也能改善ZMPSTE24(P248L或L425P)突变的MAD-B患者细胞的异常核表型。不出所料,lonafarnib并不能纠正层粘连蛋白A加工缺陷突变细胞的核缺陷。我们还研究了两个患有常见板层细胞病突变 LMNA-R644C 的人的成纤维细胞中前层粘连蛋白 A 的处理过程。尽管残基 R644 邻近前层粘蛋白 A 的裂解位点,但 R644C 患者的细胞系均未显示出前层粘蛋白 A 加工缺陷,而且两者的核形态均正常。这项研究阐明了前层粘蛋白A在各种板层病患者细胞中的加工状态和快凋素的作用,并支持FDA批准快凋素Zokinvy用于加工缺陷型原发性板层病患者,但不适用于加工缺陷型板层病患者。
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