Editing Nucleolus

{{Short description|Largest structure in the nucleus of eukaryotic cells}}
{{For|the solution concept in cooperative game theory|Nucleolus (game theory)}}
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{{Use dmy dates|date=August 2021}}
[[File:Diagram human cell nucleus.svg|thumb |292px |Nucleolus contained within the [[cell nucleus]]]]
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The '''nucleolus''' ({{IPAc-en|nj|uː|ˈ|k|l|iː|ə|l|ə|s|,_|ˌ|nj|uː|k|l|i|ˈ|oʊ|l|ə|s}}; {{plural form}}: '''nucleoli''' {{IPAc-en|-|l|aɪ}}) is the largest structure in the [[cell nucleus|nucleus]] of [[eukaryote|eukaryotic]] [[cell (biology)|cells]].<ref name="O'Sullivan-2013">{{cite journal | vauthors = O'Sullivan JM, Pai DA, Cridge AG, Engelke DR, Ganley AR | title = The nucleolus: a raft adrift in the nuclear sea or the keystone in nuclear structure? | journal = Biomolecular Concepts | volume = 4 | issue = 3 | pages = 277–86 | date = June 2013 | pmid = 25436580 | pmc = 5100006 | doi = 10.1515/bmc-2012-0043 }}</ref> It is best known as the site of [[ribosome biogenesis]]. The nucleolus also participates in the formation of [[signal recognition particle]]s and plays a role in the cell's response to stress.<ref>{{cite book | first1 = Mark OJ | last1 = Olson | first2 = Miroslav | last2 = Dundr | name-list-style = vanc | title = Encyclopedia of Life Sciences (eLS) | chapter = Nucleolus: Structure and Function | date = 16 February 2015 | doi = 10.1002/9780470015902.a0005975.pub3 | isbn = 978-0-470-01617-6 }}</ref> Nucleoli are made of [[protein]]s, [[DNA]] and [[RNA]], and form around specific chromosomal regions called [[nucleolar organizing regions]].  Malfunction of the nucleolus is the cause of several human conditions called "nucleolopathies"<ref name="Hetman-2014">{{cite journal | vauthors = Hetman M | title = Role of the nucleolus in human diseases. Preface | journal = Biochimica et Biophysica Acta | volume = 1842 | issue = 6 | pages = 757 | date = June 2014 | pmid = 24631655 | doi = 10.1016/j.bbadis.2014.03.004 | doi-access = free }}</ref><ref name="Bahadori-2022">{{cite journal |last1=Bahadori |first1=M |last2=Azizi |first2=MH |last3=Dabiri |first3=S |last4=Bahadori |first4=N |title=Effects of Human Nucleolus Upon Guest Viral-Life, Focusing in COVID-19 Infection: A Mini- Review. |journal=Iranian Journal of Pathology |date=2022 |volume=17 |issue=1 |pages=1–7 |doi=10.30699/IJP.2021.540305.2744 |pmid=35096082|pmc=8794558 }}</ref> and the nucleolus is being investigated as a target for [[cancer]] [[chemotherapy]].<ref name="Quin-2014">{{cite journal | vauthors = Quin JE, Devlin JR, Cameron D, Hannan KM, Pearson RB, Hannan RD | title = Targeting the nucleolus for cancer intervention | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1842 | issue = 6 | pages = 802–16 | date = June 2014 | pmid = 24389329 | doi = 10.1016/j.bbadis.2013.12.009 | doi-access = free | hdl = 11343/44176 | hdl-access = free }}</ref><ref name="Woods-2015">{{cite journal | vauthors = Woods SJ, Hannan KM, Pearson RB, Hannan RD | title = The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy | journal = Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | volume = 1849 | issue = 7 | pages = 821–9 | date = July 2015 | pmid = 25464032 | doi = 10.1016/j.bbagrm.2014.10.007 }}</ref>

== History ==
The nucleolus was identified by [[bright-field microscopy]] during the 1830s.<ref name="Pederson-2011">{{cite journal | vauthors = Pederson T | title = The nucleolus | journal = Cold Spring Harbor Perspectives in Biology | volume = 3 | issue = 3 | pages = a000638 | date = March 2011 | pmid = 21106648 | pmc = 3039934 | doi = 10.1101/cshperspect.a000638 }}</ref> [[Theodor Schwann]] in his 1839 treatise described that [[Matthias Jakob Schleiden|Schleiden]] had identified small corpuscles in nuclei, and named the structures "Kernkörperchen". In a 1947 translation of the work to English, the structure was named "nucleolus".<ref>{{Cite web |title=Mikroskopische Untersuchungen über die Uebereinstimmung in der Struktur und dem Wachsthum der Thiere und Pflanzen / Von Th. Schwann. Mit vier Kupfertafeln. |url=https://wellcomecollection.org/works/bknnmj2k |access-date=2024-03-12 |website=Wellcome Collection |language=en}}</ref><ref>{{Cite book |last=Schwann |first=Theodor |url=https://www.biodiversitylibrary.org/bibliography/17276 |title=Microscopical researches into the accordance in the structure and growth of animals and plants |last2=Schwann |first2=Theodor |last3=Smith |first3=Henry |last4=Schleiden |first4=M. J. |date=1847 |publisher=Sydenham Society |location=London |pages=3}}</ref>

{{Blockquote|text=In addition to these peculiarities of the cytoblast, already made known by Brown and Meyen, Schleiden has discovered in its interior a small corpuscle (see plate I, fig. 1, 4,) which, in the fully-developed cytoblast, looks like a thick ring, or a thick-walled hollow globule. It appears, however, to present a different appearance in different cytoblasts. Sometimes only the external sharply-defined circle of this ring can be distinguished, with a dark point in the centre,—occasionally, and indeed most frequently, only a sharply circumscribed spot. In other instances this spot is very small, and sometimes cannot be recognized at all. As it will frequently be necessary to speak of this body in the following treatise, I will for brevity’s sake name it the “nucleolus,” (Kernkorperchen, ‘nucleus-corpuscle.”)|author=Theodor Schwann, translated by Henry Smith|title=Microscopical Researches Into the Accordance in the Structure and Growth of Animals and Plants|source=page 3}}

Little was known about the function of the nucleolus until 1964, when a study<ref name="Brown-1964">{{cite journal | vauthors = Brown DD, Gurdon JB | title = Absence of ribosomal rna synthesis in the anucleolate mutant of xenopus laevis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 51 | issue =  1| pages = 139–46 | date = January 1964 | pmid = 14106673 | pmc = 300879 | doi = 10.1073/pnas.51.1.139 | bibcode = 1964PNAS...51..139B | doi-access = free }}</ref> of nucleoli by [[John Gurdon]] and [[Donald D. Brown|Donald Brown]] in the African clawed frog ''[[Xenopus laevis]]'' generated increased interest in its function and detailed structure. They found that 25% of the frog eggs had no nucleolus, and that such eggs were not capable of life. Half of the eggs had one nucleolus and 25% had two. They concluded that the nucleolus had a function necessary for life. In 1966, [[Max L. Birnstiel]] and collaborators showed via [[nucleic acid hybridization]] experiments that DNA within nucleoli codes for [[ribosomal RNA]].<ref name="Birnstiel-1966">{{cite journal | vauthors = Birnstiel ML, Wallace H, Sirlin JL, Fischberg M | title = Localization of the ribosomal DNA complements in the nucleolar organizer region of Xenopus laevis | journal = National Cancer Institute Monograph | volume = 23 | pages = 431–47 | date = December 1966 | pmid = 5963987 }}</ref><ref name="Wallace-1966">{{cite journal | vauthors = Wallace H, Birnstiel ML | title = Ribosomal cistrons and the nucleolar organizer | journal = Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis | volume = 114 | issue = 2 | pages = 296–310 | date = February 1966 | pmid = 5943882 | doi = 10.1016/0005-2787(66)90311-x }}</ref>

== Structure ==
Three major components of the nucleolus are recognized: the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC).<ref name="O'Sullivan-2013" /> Transcription of the [[ribosomal DNA|rDNA]] occurs in the FC.<ref name="Sirri-2008">{{cite journal | vauthors = Sirri V, Urcuqui-Inchima S, Roussel P, Hernandez-Verdun D | title = Nucleolus: the fascinating nuclear body | journal = Histochemistry and Cell Biology | volume = 129 | issue = 1 | pages = 13–31 | date = January 2008 | pmid = 18046571 | pmc = 2137947 | doi = 10.1007/s00418-007-0359-6 }}</ref> The DFC contains the protein [[fibrillarin]],<ref name="Sirri-2008" /> which is important in rRNA processing. The GC contains the protein [[NPM1|nucleophosmin]],<ref name="Sirri-2008" /> (B23 in the external image), which is also involved in [[ribosome biogenesis]].

However, it has been proposed that this particular organization is only observed in higher eukaryotes and that it evolved from a bipartite organization with the transition from [[anamniotes]] to [[amniote]]s. Reflecting the substantial increase in the DNA [[intergenic region]], an original fibrillar component would have separated into the FC and the DFC.<ref>{{cite journal | vauthors = Thiry M, Lafontaine DL | title = Birth of a nucleolus: the evolution of nucleolar compartments | journal = Trends in Cell Biology | volume = 15 | issue = 4 | pages = 194–9 | date = April 2005 | pmid = 15817375 | doi = 10.1016/j.tcb.2005.02.007 }} [http://www.lafontainelab.com/Suppl_data/Thiry_2005/S3.pdf as PDF] {{Webarchive|url=https://web.archive.org/web/20081217034953/http://www.lafontainelab.com/Suppl_data/Thiry_2005/S3.pdf |date=17 December 2008 }}</ref>
[[File:Widespread-Expression-of-BORISCTCFL-in-Normal-and-Cancer-Cells-pone.0022399.s011.ogv|thumb|Nucleus from a cell line. Fibrillarin in red. Transcription regulatory protein [[CTCFL]] in green. Nuclear DNA in blue.]]
Another structure identified within many nucleoli (particularly in plants) is a clear area in the center of the structure referred to as a nucleolar vacuole.<ref>{{cite journal | vauthors = Beven AF, Lee R, Razaz M, Leader DJ, Brown JW, Shaw PJ | title = The organization of ribosomal RNA processing correlates with the distribution of nucleolar snRNAs | journal = Journal of Cell Science | volume = 109 ( Pt 6) | issue = 6 | pages = 1241–51 | date = June 1996 | doi = 10.1242/jcs.109.6.1241 | pmid = 8799814 | url = http://jcs.biologists.org/cgi/content/short/109/6/1241 | url-access = subscription }}</ref>
Nucleoli of various plant species have been shown to have very high concentrations of iron<ref>{{cite journal | vauthors = Roschzttardtz H, Grillet L, Isaure MP, Conéjéro G, Ortega R, Curie C, Mari S | title = Plant cell nucleolus as a hot spot for iron | journal = The Journal of Biological Chemistry | volume = 286 | issue = 32 | pages = 27863–6 | date = August 2011 | pmid = 21719700 | pmc = 3151030 | doi = 10.1074/jbc.C111.269720 | doi-access = free }}</ref> in contrast to human and animal cell nucleoli.

The nucleolus [[ultrastructure]] can be seen through an [[electron microscope]], while the organization and dynamics can be studied through [[Fluorophore|fluorescent protein tagging]] and fluorescent recovery after [[photobleaching]] ([[Fluorescence recovery after photobleaching|FRAP]]). Antibodies against the PAF49 protein can also be used as a marker for the nucleolus in immunofluorescence experiments.<ref>[https://www.genetex.com/Product/Detail/PAF49-antibody/GTX102175 PAF49 antibody | GeneTex Inc]. Genetex.com. Retrieved 2019-07-18.</ref>

Although usually only one or two nucleoli can be seen, a diploid human cell has ten [[nucleolus organizer region]]s (NORs) and could have more nucleoli. Most often multiple NORs participate in each nucleolus.<ref>{{cite book | chapter = The Cell: Basic Structure and Function | title = Comprehensive Cytopathology | edition = third | vauthors = von Knebel Doeberitz M, Wentzensen N |date= 2008 }}</ref>

== Function and ribosome assembly ==
{{Main|Ribosome biogenesis}}

[[File:NucleolusNCc.jpg|thumb|Electron micrograph of part of a [[HeLa]] cell. The image is a screen capture from [https://upload.wikimedia.org/wikipedia/commons/1/11/Live-cell-immunogold-labelling-of-RNA-polymerase-II-srep08324-s2.ogv this movie], which shows a Z-stack of the cell.]]
In [[ribosome biogenesis]], two of the three eukaryotic [[RNA polymerase]]s ([[RNA polymerase I|Pol I]] and [[RNA polymerase III|Pol III]]) are required, and these function in a coordinated manner. In an initial stage, the [[Ribosomal RNA|rRNA]] genes are transcribed as a single unit within the nucleolus by [[RNA polymerase I]]. In order for this transcription to occur, several pol I-associated factors and DNA-specific trans-acting factors are required. In [[yeast]], the most important are: UAF ([[upstream activating factor]]), [[TATA Binding Protein|TBP]] (TATA-box binding protein), and [[core binding factor]] (CBF), which bind promoter elements and form the [[Transcription preinitiation complex|preinitiation complex]] (PIC), which is in turn recognized by RNA polymerase. In humans, a similar PIC is assembled with [[selective factor 1|SL1]], the promoter selectivity factor (composed of TBP and [[TBP-associated factor]]s, or TAFs), transcription initiation factors, and [[UBTF|UBF]] (upstream binding factor). RNA polymerase I transcribes most rRNA transcripts ([[28S ribosomal RNA|28S]], [[18S ribosomal RNA|18S]], and [[5.8S ribosomal RNA|5.8S]]), but the [[5S ribosomal RNA|5S]] rRNA subunit (component of the 60S ribosomal subunit) is transcribed by RNA polymerase III.<ref>{{cite book  |first1=Pamela C. |last1=Champe |first2=Richard A. |last2=Harvey |first3=Denise R. |last3=Ferrier | name-list-style = vanc |title=Lippincott's Illustrated Reviews: Biochemistry |url=https://books.google.com/books?id=M_YOW50cg9oC |year=2005 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-2265-0}}</ref>

Transcription of rRNA yields a long precursor molecule ([[45S pre-rRNA]]), which still contains the [[internal transcribed spacer]] (ITS) and [[external transcribed spacer]] (ETS). Further processing is needed to generate the 18S RNA, 5.8S, and 28S RNA molecules. In eukaryotes, the RNA-modifying enzymes are brought to their respective [[recognition site]]s by interaction with guide RNAs, which bind these specific sequences.  These guide RNAs belong to the class of small nucleolar RNAs ([[snoRNA]]s), which are complexed with proteins and exist as small-nucleolar-[[ribonucleoprotein]]s ([[snoRNP]]s). Once the rRNA subunits are processed, they are ready to be assembled into larger ribosomal subunits. However, an additional rRNA molecule, the 5S rRNA, is also necessary. In yeast, the 5S rDNA sequence is localized in the intergenic spacer and is transcribed in the nucleolus by RNA polymerase.

In higher [[eukaryote]]s and plants, the situation is more complex, for the 5S DNA sequence lies outside the NOR and is transcribed by RNA Pol III in the [[nucleoplasm]], after which it finds its way into the nucleolus to participate in the ribosome assembly. This assembly not only involves the rRNA, but also [[ribosomal protein]]s. The genes encoding these r-proteins are transcribed by Pol II in the nucleoplasm by a "conventional" pathway of protein synthesis (transcription, pre-mRNA processing, nuclear export of mature mRNA, and [[translation (biology)|translation]] on cytoplasmic ribosomes). The mature r-proteins are then imported into the nucleus and, finally, the nucleolus. Association and maturation of rRNA and r-proteins result in the formation of the 40S (small) and 60S (large) subunits of the complete ribosome. These are exported through the [[nuclear pore complex]]es to the cytoplasm, where they remain free or become associated with the [[endoplasmic reticulum]], forming the [[rough endoplasmic reticulum]] (RER).<ref name="Alberts-2002">{{cite book |first1=Bruce |last1=Alberts |first2=Alexander |last2=Johnson |first3=Julian |last3=Lewis |first4=Martin |last4=Raff |first5=Keith |last5=Roberts |first6=Peter |last6=Walter | name-list-style = vanc |title=Molecular Biology of the Cell |publisher=Garland Science |location=New York |year=2002 |isbn=978-0-8153-3218-3 |pages=331–3 |url=https://www.ncbi.nlm.nih.gov/books/NBK21054/ |edition=4th}}</ref><ref name="Cooper-2007">{{cite book |first1=Geoffrey M. |last1=Cooper |first2=Robert E. |last2=Hausman | name-list-style = vanc |title=The Cell: A Molecular Approach |publisher=Sinauer Associates |year=2007 |isbn=978-0-87893-220-7 |pages=371–9 |edition=4th}}</ref>

In human [[Endometrium|endometrial cells]], a network of nucleolar channels is sometimes formed. The origin and function of this network have not yet been clearly identified.<ref>{{cite journal|last1=Wang|first1=Tzuneng|last2=Schneider|first2=J | name-list-style = vanc |title=Origin and fate of the nucleolar channel system of normal human endometrium|journal=Cell Research|date=1 July 1992|volume=2|issue=2|pages=97–102|doi=10.1038/cr.1992.10|doi-access=free}}</ref>

== Sequestration of proteins ==
In addition to its role in ribosomal biogenesis, the nucleolus is known to capture and immobilize proteins, a process known as nucleolar detention. Proteins that are [[Detention center (cell biology)|detained in the nucleolus]] are unable to diffuse and to interact with their binding partners. Targets of this [[Post-translational regulation|post-translational regulatory mechanism]] include [[Von Hippel–Lindau tumor suppressor|VHL]], [[Promyelocytic leukemia protein|PML]], [[MDM2]], [[POLD1]], [[RELA|RelA]], [[HAND1]] and [[Telomerase reverse transcriptase|hTERT]], among many others. It is now known that [[long noncoding RNA]]s originating from [[intergenic region]]s of the nucleolus are responsible for this phenomenon.<ref>{{cite journal | vauthors = Audas TE, Jacob MD, Lee S | title = Immobilization of proteins in the nucleolus by ribosomal intergenic spacer noncoding RNA | journal = Molecular Cell | volume = 45 | issue = 2 | pages = 147–57 | date = January 2012 | pmid = 22284675 | doi = 10.1016/j.molcel.2011.12.012 | doi-access = free }}</ref>

== See also ==
*[[Differential interference contrast microscopy]]

== References ==
{{Reflist|32em}}

== Further reading ==
{{refbegin}}
* {{cite book |first=Geoffrey M. |last=Cooper | name-list-style = vanc |chapter=The Nucleolus |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK9939/ |title=The Cell: A Molecular Approach |publisher=Sinauer Associates |location=Sunderland MA |year=2000 |isbn=978-0-87893-106-4 |url=https://www.ncbi.nlm.nih.gov/books/NBK9839/ |edition=2nd}}
* {{cite journal | vauthors = Tiku V, Antebi A | title = Nucleolar Function in Lifespan Regulation | journal = Trends in Cell Biology | volume = 28 | issue = 8 | pages = 662–672 | date = August 2018 | pmid = 29779866 | doi = 10.1016/j.tcb.2018.03.007 | s2cid = 29167518}}
**{{cite news |author=JoAnna Klein |date=20 May 2018 |title=The Thing Inside Your Cells That Might Determine How Long You Live |newspaper=The New York Times |url=https://www.nytimes.com/2018/05/20/science/nucleolus-cells-aging.html |url-access=subscription}}
{{refend}}

== External links ==
{{Commons category|Cell nucleolus}}
{{Wiktionary|nucleolus}}
* [http://www.uni-mainz.de/FB/Medizin/Anatomie/workshop/EM/EMNucleolus.html Nucleolus under electron microscope II at uni-mainz.de]
* [http://npd.hgu.mrc.ac.uk/user/compartment?page=nucleolus.html Nuclear Protein Database – search under compartment]
* {{MeshName|Cell+Nucleolus}}
* {{BUHistology|20104loa}}
{{organelles}}
{{Nucleus}}
{{Authority control}}

[[Category:Organelles]]
[[Category:Nuclear substructures]]