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Nucleolus: a Central Hub for Nuclear Functions Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, Sergey Razin, Yegor Vassetzky

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Nucleolus: a Central Hub for Nuclear Functions Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, Sergey Razin, Yegor Vassetzky Nucleolus: A Central Hub for Nuclear Functions Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, Sergey Razin, Yegor Vassetzky To cite this version: Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, et al.. Nucleolus: A Central Hub for Nuclear Functions. Trends in Cell Biology, Elsevier, 2019, 29 (8), pp.647-659. 10.1016/j.tcb.2019.04.003. hal-02322927 HAL Id: hal-02322927 https://hal.archives-ouvertes.fr/hal-02322927 Submitted on 18 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Nucleolus: A Central Hub for Nuclear Functions Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, Sergey Razin, Yegor Vassetzky To cite this version: Olga Iarovaia, Elizaveta Minina, Eugene Sheval, Daria Onichtchouk, Svetlana Dokudovskaya, et al.. Nucleolus: A Central Hub for Nuclear Functions. Trends in Cell Biology, Elsevier, 2019, 29 (8), pp.647-659. 10.1016/j.tcb.2019.04.003. hal-02322927 HAL Id: hal-02322927 https://hal.archives-ouvertes.fr/hal-02322927 Submitted on 18 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Trends in Cell Biology Nucleolus: a central hub for nuclear functions --Manuscript Draft-- Manuscript Number: TCB-D-18-00157R1 Article Type: Review Keywords: nucleolus; nuclear compartmentalization; protein shuttling; 3D genome organization; DNA repair and recombination; transcription Corresponding Author: Yegor Vassetzky, Ph.D., D.Sc. CNRS Villejuif, IdF FRANCE First Author: Olga V. Iarovaia Order of Authors: Olga V. Iarovaia Elizaveta P. Minina Eugene V. Sheval Daria Onichtchouk Svetlana Dokudovskaya Sergey V. Razin Yegor Vassetzky, Ph.D., D.Sc. Abstract: The nucleus contains distinct nuclear bodies (NBs); nucleolus is the largest and the most studied NB, but its role in the functioning of the nucleus is far from being fully understood. The nucleolus is not surrounded by a membrane, yet it contains DNA, RNA and a set of proteins that can either be retained in the nucleolus or rapidly shuttle between the nucleoplasm, the nucleolus and the cytoplasm in response to various stimuli. The emerging evidence points to the central function of the nucleolus in organizing many nuclear functions besides RNA polymerase I transcription and ribosome biogenesis. Here we discuss the functions of the nucleolus related to the shuttling of proteins and nucleic acids between nucleolus and nucleoplasm. The functional processes affected by shuttling of nucleolar components include 3D organization of the genome, stress response, DNA repair and recombination, transcription regulation, telomere maintenance and other essential cellular functions. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Highlights Highlights Nucleolus is a PolI transcription factory and a place of ribosome assembly, but is also performs many other functions that are commonly referred to as non-canonical functions of nucleolus Nucleolus organizes the adjacent chromatin into a large-scale repressive hub underlying the spatial segregation of active and repressive chromatin compartments. The interphase chromosomes are attached to the nucleolus via nucleolus-associated domains (NADs). Protein shuttling between the nucleolus and the nucleoplasm regulates a multitude of nuclear processes including DNA repair, recombination, transcription and telomere maintenance. Sequestration of proteins within nucleolus allows decrease sharply their concentration within other cellular compartments. Perinucleolar regions contain a recombination compartment; they also participate in allelic exclusion and X chromosome silencing. Manuscript Click here to access/download;Manuscript;Nucleolus TCB v4.doc Nucleolus: a central hub for nuclear functions Olga V. Iarovaia1,2,*, Elizaveta P. Minina3,*, Eugene V. Sheval2,4,5,*, Daria Onichtchouk6, Svetlana Dokudovskaya2,8 , Sergey V. Razin1,2,5 and Yegor S. Vassetzky2,7,8,9 1Institute of Gene Biology of the Russian Academy of Sciences, 119334 Moscow, Russia 2LIA 1066 LFR2O French-Russian Joint Cancer Research Laboratory, 94805 Villejuif, France 3Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia 4Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia 5Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia 6Developmental Biology Unit, Department of Biology I, University of Freiburg, Hauptstrasse 1, D-79104 Freiburg, Germany 7Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, 119334 Moscow, Russia 8UMR8126, Université Paris-Sud, CNRS, Institut Gustave Roussy, 94805 Villejuif, France 9Corrsponding author *equal contribution Keywords: Nuclear compartmentalization, nucleolus, 3D genome organization, DNA repair and recombination, transcription Word count: 3843 1 Summary The nucleolus is the largest and the most studied nuclear body, but its role in nuclear function is far from understood. Much work on the nucleolus has focused on its role in regulating RNA polymerase I transcription and ribosome biogenesis; however, emerging evidence points to the nucleolus as an organizing hub for many nuclear functions accomplished via shuttling of proteins and nucleic acids between the nucleolus and nucleoplasm. Here we discuss the cellular mechanisms affected by shuttling of nucleolar components that include 3D organization of the genome, stress response, DNA repair and recombination, transcription regulation, telomere maintenance and other essential cellular functions. 2 Glossary Allelic exclusion: a situation when one allele of a given gene is expressed while the other allele is transcriptionally inactive. Hi-C: a high-throughput method to study the three-dimensional architecture of genomes based on proximity ligation. Nucleolus-associated domains (NADs): chromatin domains that dynamically interact with nucleoli. Nucleolar localization signals (NoLS): a short protein sequence allowing to localize a protein inside the nucleolus. NoLS do not have a consensus sequence, but they are constantly enriched with positively charged amino acids. As a result, nucleolar accumulation via NoLS is dependent on the overall charge of the signal region. Protein shuttling: most nuclear proteins are not tightly associated with nuclear bodies, but rather are continuously exchanged between these bodies and the surrounding nucleoplasm. This mobility allows these proteins to quickly relocalize between different nuclear domains, leading to unprecedented plasticity of the genome functioning. Sequestration: mobile, continuously exchanging proteins can increase their concentration inside a nuclear body under some conditions. This process referred to as protein sequestration may be driven either by appearance of novel binding sites for the protein inside nucleoli, or disappearance of binding sited outside nucleoli, or posttranslational modifications of protein (or a combination thereof). Sequestration may also be due to a decrease of protein exchange due to 3 tight association with a component(s) inside any subcellular structure (protein immobilization) or due to formation of protein aggregates. Stress response: a reaction which dedicates energy and effort to acute adaptation to stress. Topologically associating domain (TAD): a genomic region where DNA sequences physically interact with each other with a higher frequency as compared to the sequences outside the TAD. In mammals, TAD boundaries are enriched in CTCF/Cohesin binding sites. Most interactions observed between gene enhancers and promoters occur within one TAD. TADs were shown to coincide with replication domains. 4 Introduction The main function of the nucleolus is the synthesis and processing of rRNA and ribosome assembly. Nucleoli contain clusters of ribosomal RNA genes (rDNA) and their transcripts (rRNA) (reviewed in [1]), as well as several hundred proteins participating in many nuclear processes inside and outside the nucleolus [2]. Recent data on nucleolar proteins and the analysis of genomic DNA loci associated with the nucleolus suggest that the function of the nucleolus is not limited to ribosome biogenesis, and that the nucleolus plays a role of a central hub regulating many nuclear and cellular processes. Movement of chromatin vs. the nucleolus may trigger activation and silencing of gene transcription [3,4], mediate inactivation of chromatin domains [5], underlie allelic exclusion, and spatially organize gene recombination [6]. In
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