{"id":17098,"date":"2019-08-20T17:00:59","date_gmt":"2019-08-20T15:00:59","guid":{"rendered":"https:\/\/news.embl.de\/?p=17098"},"modified":"2024-03-22T10:53:46","modified_gmt":"2024-03-22T09:53:46","slug":"kissing-loops-in-lncrna","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science\/kissing-loops-in-lncrna\/","title":{"rendered":"MEG3 kissing loops essential for tumour suppression"},"content":{"rendered":"\n

A team of researchers in the Marcia group at EMBL Grenoble have discovered that the tumour suppressor MEG3 adopts a complex three-dimensional structure to fulfil its function. Furthermore, they were able to fine-tune its activity by targeted manipulation of this architecture. The results of this study, published in Molecular Cell<\/em>, might help to advance diagnosis and treatment of certain types of cancer.<\/p>\n\n\n\n

The power and mystery of MEG3<\/h2>\n\n\n\n

Human cells \u2013 like those of many other organisms \u2013 have developed mechanisms to protect us from cancer. Healthy cells produce a suite of molecules that stop harmful mutations from accumulating. The most famous guardian of our genome is the protein p53: whenever p53 becomes inactive or is malfunctioning, the risk of developing cancer increases sharply. MEG3, which has been studied in detail by Marco Marcia and his group at EMBL Grenoble, is another cancer-preventing molecule that our cells produce. Its function arises from stimulating p53. However, unlike p53, MEG3 is not a protein and belongs to a class of RNA molecules discovered within the last 20 years, called long non-coding RNAs; lncRNAs for short. While human cells likely contain more lncRNAs than proteins, the biological importance and mechanisms of action of these RNAs remain largely obscure. Some lncRNAs, like MEG3, are linked to diseases, but scientists have not been able to decipher how they work exactly. This has triggered scepticism among some researchers in the field, says Marcia: \u201cBecause of the lack of molecular understanding of how lncRNAs work, many scientists still question the actual functional relevance of these molecules.\u201d <\/strong><\/p>\n\n\n\n

Why shape and function are interlinked<\/h2>\n\n\n\n

Marcia\u2019s aim was to change this perception, by studying the three-dimensional shape of lncRNAs. He and his group hope that knowing more about lncRNA structures will help to understand how these molecules function. \u201c3D structures provide the molecular map, the molecular cartography of biological molecules. When one visits a new city, one wants to know where the railway station is, where the city hall, the schools, the parks are, because those are the elements of the city that make it function properly. The same is true for biomolecules: you want to know how they are folded and structured so that you can identify their functional units,\u201d says Marcia.  Using biochemistry, cell biology and single-particle atomic force microscopy, the team studied the structure of MEG3 in great detail. The group systematically removed and modified the building blocks of MEG3, to find out which of them are essential for its functionality. This way, the researchers discovered two elements inside the molecule that are more important for its function as a tumour suppressor than others. Interestingly, these elements form hairpin structures, which biologists call \u2018kissing loops\u2019, that interact with each other in three dimensions. When these kissing loops were disrupted by manipulating the building blocks of MEG3, the tumour suppression function of MEG3 was also disrupted. The findings of the group might have wider implications, explains Marcia: \u201cThe fact that the 3D structure of lncRNAs is important sheds new light on these molecules. It shows that lncRNA molecules are much more sophisticated than we thought, because they need to be controlled and folded very precisely to work properly.\u201d <\/strong><\/p>\n\n\n\n

Improving diagnosis and treatment of brain cancer<\/h2>\n\n\n\n

MEG3 is abundant in different mammalian tissues, particularly the brain and endocrine glands like the pituitary gland. Tumours in the brain and the pituitary gland can develop when MEG3 is not working properly. To date, these types of tumours can only be treated by surgery. One way of overcoming the need for invasive surgery would be to stimulate MEG3 activity in the tumour.  Designing drugs that stabilise the MEG3 kissing loops might improve its tumour suppressor function to the point where it can arrest tumour growth. Knowledge about the composition of healthy MEG3 might also help to identify people with abnormally folded MEG3 who are at higher risk of developing cancer.<\/p>\n\n\n\n

The unsolved mysteries around MEG3 and other lncRNAs<\/h2>\n\n\n\n

Despite their meticulous work, the group has not solved the whole puzzle surrounding MEG3, emphasises Marcia: \u201cWe still need to discover the precise order of events that lead to MEG3-dependent activation and stimulation of p53.\u201d The results provided in this new paper, which also includes contributions from colleagues at the Institut de Biologie Structurale (Grenoble), the Department CIBIO (University of Trento) and the Max Delbr\u00fcck Center (Berlin), present the most detailed molecular insight into a lncRNA to date, but trigger the question whether 3D structures are equally important for the function of other lncRNAs. Marcia and his group want to continue analysing the structure and function of further lncRNAs. However, it will be impossible for them alone to study the many thousands of lncRNAs that human cells produce. \u201cI truly hope that the methods and experimental approach we have followed will stimulate other colleagues in the community and help us expand the characterisation of lncRNAs,\u201d says Marcia.<\/p>\n\n\n\n

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\u2018Des boucles s\u2019embrassant\u2019 dans une mol\u00e9cule d\u2019ARN, indispensables \u00e0 son r\u00f4le dans la suppression de tumeurs<\/strong><\/h2>\n\n\n\n

Une \u00e9quipe de chercheurs du groupe Marcia \u00e0 l\u2019EMBL Grenoble, France, a d\u00e9couvert que le suppresseur de tumeur MEG3 adopte une structure tri-dimensionnelle complexe pour accomplir sa fonction. En outre, ils ont \u00e9t\u00e9 en mesure d\u2019affiner son activit\u00e9 par une manipulation cible de son architecture. Les r\u00e9sultats de cette \u00e9tude, publi\u00e9e dans Molecular Cell, peuvent peut-\u00eatre aider \u00e0 faire progresser le diagnostic et le traitement de certains types de cancer.<\/p>\n\n\n\n

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IMAGE: illustratoren.de\/TobiasWuestefeld<\/figcaption><\/figure>\n\n\n\n

La puissance et le myst\u00e8re de MEG3<\/strong><\/h2>\n\n\n\n

Les cellules humaines, comme celles de nombreux organismes, ont d\u00e9velopp\u00e9 des m\u00e9canismes pour nous prot\u00e9ger du cancer. Les cellules saines produisent une suite de mol\u00e9cules qui emp\u00eachent les mutations nocives de s\u2019accumuler. La gardienne la plus connue de notre g\u00e9nome est la prot\u00e9ine p53 : quand p53 devient inactive ou ne fonctionne pas correctement, le risque de d\u00e9velopper un cancer augmente fortement. MEG3, qui a \u00e9t\u00e9 \u00e9tudi\u00e9e en d\u00e9tail par Marco Marcia et son groupe \u00e0 l\u2019EMBL, Grenoble, est une autre mol\u00e9cule permettant d\u2019\u00e9viter le cancer que nos cellules produisent. Sa fonction d\u00e9coule de la stimulation de p53. Toutefois, contrairement \u00e0 p53, MEG3 n\u2019est pas une prot\u00e9ine et appartient \u00e0 une classe de mol\u00e9cules ARN d\u00e9couvertes au cours des 20 derni\u00e8res ann\u00e9es, appel\u00e9e les ARN non codantes longues ; ARNlnc en abr\u00e9g\u00e9.<\/p>\n\n\n\n

Alors que les cellules humaines ont tendance \u00e0 contenir plus d\u2019ARNlnc que de prot\u00e9ines, l\u2019importance biologique et les m\u00e9canismes d\u2019action de ces ARN restent grandement obscures. Certaines ARNlnc, comme MEG3, sont li\u00e9es aux maladies, mais les scientifiques n\u2019ont pas \u00e9t\u00e9 capables de d\u00e9chiffrer comment ces ARNs fonctionnent exactement. Ceci a d\u00e9clench\u00e9 un scepticisme parmi certains chercheurs dans ce domaine, d\u00e9clare Marcia : \u201cEn raison du manque de compr\u00e9hension mol\u00e9culaire de la fa\u00e7on dont les ARNlnc fonctionnent, de nombreux scientifiques questionnent encore la pertinence fonctionnelle actuelle de ces mol\u00e9cules.\u201d<\/p>\n\n\n\n

Pourquoi la forme et la fonction sont interconnect\u00e9es<\/strong><\/h2>\n\n\n\n

L\u2019objectif de Marcia \u00e9tait de changer cette perception, en \u00e9tudiant la forme tri-dimensionnelle des ARNlnc. Marcia et son groupe esp\u00e8rent que le fait d\u2019en savoir plus sur les structures ARNlnc aidera \u00e0 comprendre la fa\u00e7on dont ces mol\u00e9cules fonctionnent.<\/p>\n\n\n\n

\u201cLes structures 3D fournissent la carte mol\u00e9culaire, la cartographie mol\u00e9culaire des mol\u00e9cules biologiques. Quand on visite une nouvelle ville, on cherche \u00e0 savoir o\u00f9 se trouvent la gare, la mairie, les \u00e9coles, les parcs, parce que ce sont les \u00e9l\u00e9ments de la ville qui la font fonctionner correctement. C\u2019est de m\u00eame pour les bio mol\u00e9cules : on cherche \u00e0 savoir comment elles sont repli\u00e9es et structur\u00e9es afin de pouvoir identifier leurs unit\u00e9s fonctionnelles, \u201d dit Marcia.<\/p>\n\n\n\n

En utilisant la biochimie, la biologie cellulaire et la microscopie de force atomique \u00e0 particule unique, l\u2019\u00e9quipe a \u00e9tudi\u00e9 la structure de MEG3 dans tous ses d\u00e9tails. Le groupe a syst\u00e9matiquement retir\u00e9 et modifi\u00e9 les blocs de construction de MEG3 afin de d\u00e9couvrir lesquels sont essentiels pour sa fonctionnalit\u00e9. C\u2019est ainsi que les chercheurs ont d\u00e9couvert deux \u00e9l\u00e9ments \u00e0 l\u2019int\u00e9rieur de la mol\u00e9cule qui sont plus importants que les autres pour sa fonction en tant que suppresseur de tumeur. Ce qui est int\u00e9ressant, c\u2019est que ces \u00e9l\u00e9ments forment des structures en \u00e9pingle \u00e0 cheveux, que les biologistes appellent \u00ab Boucles s\u2019embrassant \u00bb, qui interagissent les unes avec les autres dans trois dimensions.<\/p>\n\n\n\n

Quand ces boucles s\u2019embrassant \u00e9taient interrompues par la manipulation des blocs de construction de MEG3, la fonction de suppression de la tumeur de MEG3 \u00e9tait aussi interrompue. Les d\u00e9couvertes du groupe peuvent avoir des implications plus larges, explique Marcia : \u201cLe fait que la structure 3D des ARNlnc est importante jette un nouvel \u00e9clairage sur ces mol\u00e9cules. Cela montre que les ARNlnc sont beaucoup plus sophistiqu\u00e9es que nous pensons, car elles ont besoin d\u2019\u00eatre contr\u00f4l\u00e9es et repli\u00e9es tr\u00e8s pr\u00e9cis\u00e9ment afin de fonctionner correctement.\u201d<\/p>\n\n\n\n

Am\u00e9liorer le diagnostic et le traitement du cancer du cerveau<\/strong><\/h2>\n\n\n\n

MEG3 est une mol\u00e9cule abondante dans diff\u00e9rents tissus mammaliens, en particulier le cerveau et les glandes endocrines comme l\u2019hypophyse. Des tumeurs dans le cerveau et l\u2019hypophyse peuvent se d\u00e9velopper quand MEG3 ne fonctionne pas correctement. A cette date, ces types de tumeurs ne peuvent \u00eatre trait\u00e9es que par la chirurgie. Une fa\u00e7on de d\u00e9passer le besoin d\u2019une chirurgie invasive serait de stimuler l\u2019activit\u00e9 de MEG3 dans la tumeur.<\/p>\n\n\n\n

Concevoir des m\u00e9dicaments qui stabilisent les boucles s\u2019embrassant de MEG3 pourrait am\u00e9liorer sa fonction de suppresseur de tumeur au point qu\u2019elle pourrait stopper la croissance de la tumeur. Les connaissances relatives \u00e0 la composition de MEG3 saines pourraient \u00e9galement aider \u00e0 identifier les personnes ayant des MEG3 repli\u00e9es de fa\u00e7on anormale qui pr\u00e9sentent donc un risque plus important de d\u00e9velopper un cancer. <\/p>\n\n\n\n

Les myst\u00e8res non r\u00e9solus autour de MEG3 et autres ARNlnc<\/strong><\/h2>\n\n\n\n

Malgr\u00e9 son travail m\u00e9ticuleux, le groupe n\u2019a pas r\u00e9solu l\u2019ensemble de l\u2019\u00e9nigme entourant MEG3, souligne Marcia : \u201cNous avons encore besoin de d\u00e9couvrir l\u2019ordre pr\u00e9cis des \u00e9v\u00e9nements qui m\u00e8nent \u00e0 l\u2019activation et \u00e0 la stimulation de p53 de la part de MEG3.\u201d<\/p>\n\n\n\n

Les r\u00e9sultats fournis dans ce nouvel article, qui comprend aussi les contributions de coll\u00e8gues de l\u2019Institut de Biologie Structurale (Grenoble), du d\u00e9partement CIBIO (Universit\u00e9 de Trente) et du Max Delbr\u00fcck Center (Berlin), pr\u00e9sentent les informations approfondies mol\u00e9culaires les plus d\u00e9taill\u00e9es dans une ARNlnc \u00e0 ce jour, mais soul\u00e8vent des questions pour savoir si les structures 3D sont tout aussi importantes pour la fonction d\u2019autres ARNlnc. Marcia et son groupe veulent continuer \u00e0 analyser la structure et la fonction d\u2019autres ARNlnc. Il sera toutefois impossible pour eux seuls d\u2019\u00e9tudier les nombreux milliers d\u2019ARNlnc que les cellules humaines produisent. \u201cJ\u2019esp\u00e8re vraiment que les m\u00e9thodes et l\u2019approche exp\u00e9rimentale que nous avons suivies stimuleront d\u2019autres coll\u00e8gues dans la communaut\u00e9 pour prendre le relais de notre \u00e9tude et nous aider \u00e0 \u00e9tendre la caract\u00e9risation des IncRNA,\u201d dit Marcia. <\/p>\n\n\n\n

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\u2018K\u00fcssende Schleifen’ in RNA-Molek\u00fcl essentiell f\u00fcr Tumorunterdr\u00fcckung<\/strong><\/h2>\n\n\n\n

Ein Forscherteam am EMBL Grenoble, Frankreich, hat entdeckt, dass der Tumorsuppressor MEG3 eine komplexe dreidimensionale Struktur annimmt, um seine Funktion zu erf\u00fcllen. Dar\u00fcber hinaus konnten sie seine Aktivit\u00e4ten durch gezielte Manipulation dieser Architektur verfeinern. Die Ergebnisse dieser Studie, die in der Zeitschrift Molecular Cell ver\u00f6ffentlicht wurden, k\u00f6nnten dabei helfen, die Diagnose und Behandlung bestimmter Krebsarten voranzutreiben.<\/p>\n\n\n\n

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BILD: illustratoren.de\/TobiasWuestefeld<\/figcaption><\/figure>\n\n\n\n

Die Kraft und das Geheimnis von MEG3<\/strong><\/h2>\n\n\n\n

Menschliche Zellen haben \u2013 wie viele andere Organismen auch \u2013 Mechanismen entwickelt, um uns vor Krebs zu sch\u00fctzen. Gesunde Zellen produzieren eine Reihe von Molek\u00fclen, die das Ansammeln sch\u00e4dlicher Mutationen verhindern. Der bekannteste H\u00fcter unseres Genoms ist das Protein p53: Wenn p53 inaktiv wird oder nicht mehr richtig funktioniert, steigt das Risiko, Krebs zu entwickeln, stark an. MEG3, das von Marco Marcia und seiner Gruppe am EMBL Grenoble ausf\u00fchrlich untersucht wurde, ist ein weiteres krebspr\u00e4ventives Molek\u00fcl, das unsere Zellen produzieren. Seine Funktion ergibt sich aus der Stimulation von p53. Im Gegensatz zu p53 ist MEG3 jedoch kein Protein und geh\u00f6rt zu einer Klasse von RNA-Molek\u00fclen, die in den letzten 20 Jahren entdeckt wurden, den sogenannten langen nichtcodierenden RNAs; kurz lncRNAs.<\/p>\n\n\n\n

W\u00e4hrend menschliche Zellen wahrscheinlich mehr lncRNAs als Proteine enthalten, sind die biologische Bedeutung und die Wirkmechanismen dieser RNAs noch weitgehend unklar. Einige lncRNAs, wie MEG3, sind mit Krankheiten verbunden, aber Wissenschaftler konnten bisher nicht entschl\u00fcsseln, wie sie genau funktionieren. Dies hat bei einigen Forschern Skepsis ausgel\u00f6st, sagt Marcia: “Aufgrund des fehlenden molekularen Verst\u00e4ndnisses der Funktionsweise von lncRNAs stellen viele Wissenschaftler immer noch die tats\u00e4chliche funktionelle Relevanz dieser Molek\u00fcle in Frage.”<\/p>\n\n\n\n

Warum Form und Funktion miteinander verkn\u00fcpft sind<\/strong><\/h2>\n\n\n\n

Marcia’s Ziel war es, diese Wahrnehmung zu \u00e4ndern, indem er die dreidimensionale Form von lncRNAs studierte. Er und seine Gruppe hoffen, dass das Wissen um die lncRNA-Strukturen helfen wird, zu verstehen, wie diese Molek\u00fcle funktionieren.<\/p>\n\n\n\n

“3D-Strukturen liefern die molekulare Karte, die molekulare Kartographie biologischer Molek\u00fcle. Wenn man eine Stadt zum ersten Mal besucht, will man wissen, wo der Bahnhof ist, wo sich das Rathaus, die Schulen, die Parks befinden. Denn das sind die Elemente der Stadt, die sie zum Funktionieren bringen. Das Gleiche gilt f\u00fcr Biomolek\u00fcle: Man will wissen, wie sie gefaltet und strukturiert sind, damit man ihre funktionierenden Einheiten identifizieren kann,” sagt Marcia.<\/p>\n\n\n\n

Mit Hilfe von Biochemie, Zellbiologie und Rasterkraftmikroskopie untersuchte das Team die Struktur von MEG3. Systematisch wurden die Bausteine von MEG3 entfernt und modifiziert, um herauszufinden, welche von ihnen wesentlich f\u00fcr ihre Funktionalit\u00e4t sind. Auf diese Weise entdeckten die Forscher zwei Elemente im Inneren des Molek\u00fcls, die f\u00fcr seine Funktion als Tumorsuppressor wichtiger sind als andere. Interessanterweise bilden diese Elemente Haarnadelstrukturen, die von Biologen als Kissing Loops (“k\u00fcssende Schleifen”) bezeichnet werden und die dreidimensional miteinander interagieren.<\/p>\n\n\n\n

Als diese Kissing Loops durch Manipulation der Bausteine von MEG3 gest\u00f6rt wurden, wurde auch die Tumorunterdr\u00fcckungsfunktion von MEG3 gest\u00f6rt. Die Erkenntnisse der Forschergruppe k\u00f6nnten weitreichende Auswirkungen haben, erkl\u00e4rt Marcia: “Die Tatsache, dass die 3D-Struktur von lncRNAs wichtig ist, wirft ein neues Licht auf diese Molek\u00fcle. Es zeigt, dass lncRNA-Molek\u00fcle viel komplexer sind, als wir dachten, denn sie m\u00fcssen kontrolliert und sehr pr\u00e4zise gefaltet werden, um richtig zu funktionieren.”<\/p>\n\n\n\n

Verbesserung der Diagnose und Behandlung von Hirnkrebs<\/strong><\/h2>\n\n\n\n

MEG3 ist in verschiedenen Geweben von S\u00e4ugetieren reichlich vorhanden \u2013 insbesondere im Gehirn und in den endokrinen Dr\u00fcsen wie der Hypophyse. Tumore im Gehirn und in der Hypophyse k\u00f6nnen entstehen, wenn MEG3 nicht richtig funktioniert. Bislang k\u00f6nnen diese Tumorarten nur operativ behandelt werden. Eine M\u00f6glichkeit, die Notwendigkeit einer invasiven Operation zu umgehen, w\u00e4re die Stimulierung der MEG3-Aktivit\u00e4t im Tumor.<\/p>\n\n\n\n

Die Entwicklung von Medikamenten, die die MEG3- Kissing Loops stabilisieren, k\u00f6nnte die Funktion des Tumorsuppressors so weit verbessern, dass er das Tumorwachstum stoppen kann. Das Wissen \u00fcber die Zusammensetzung von gesundem MEG3 k\u00f6nnte auch dabei helfen, Menschen mit abnormal gefaltetem MEG3 \u2013 und damit einem h\u00f6heren Krebsrisiko \u2013 zu identifizieren. <\/p>\n\n\n\n

Die ungel\u00f6sten R\u00e4tsel um MEG3 und andere lncRNAs<\/strong><\/h2>\n\n\n\n

Trotz ihrer akribischen Arbeit hat die Gruppe nicht das gesamte R\u00e4tsel um MEG3 gel\u00f6st, wie Marcia betont: “Wir m\u00fcssen noch den genauen Ablauf der Ereignisse herausfinden, die zu einer MEG3-abh\u00e4ngigen Aktivierung und Stimulation von p53 f\u00fchren.”<\/p>\n\n\n\n

Die enthaltenen Ergebnisse in der Publikation \u2013 an der auch Wissenschaftler vom Institut de Biologie Structurale (Grenoble), der Abteilung CIBIO (Universit\u00e4t Trento) und des Max-Delbr\u00fcck-Centers (Berlin) mitgearbeitet haben \u2013 stellen den bisher detailliertesten molekularen Einblick in eine lncRNA dar. Gleichzeitig f\u00fchren sie aber zu der Frage, ob 3D-Strukturen f\u00fcr die Funktion anderer lncRNAs ebenso wichtig sind. Marcia und seine Gruppe wollen die Struktur und Funktion anderer lncRNAs weiter analysieren. Allerdings wird es f\u00fcr sie allein unm\u00f6glich sein, die vielen tausend lncRNAs zu untersuchen, welche von menschlichen Zellen produziert werden. “Ich hoffe sehr, dass die Methoden und der experimentelle Ansatz, den wir verfolgt haben, andere Kollegen in der Gemeinschaft dazu anregen werden, den Staffelstab aus unserer Studie zu \u00fcbernehmen und uns zu helfen, die Charakterisierung von lncRNAs zu erweitern”, sagt Marcia. <\/p>\n\n\n\n

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I \u201ckissing loop\u201d di una molecoa di RNA sono fondamentali per la sua funzione di soppressore tumorale<\/strong><\/h2>\n\n\n\n

Un team di ricercatori appartenente al gruppo Marcia presso il Laboratorio Europeo di Biologia Molecolare (EMBL) di Grenoble, in Francia, ha scoperto che l\u2019oncosoppressore MEG3 adotta una complessa struttura tridimensionale per svolgere il proprio compito. Il team \u00e8 inoltre riuscito a investigarne pi\u00f9 approfonditamente il funzionamento, tramite una manipolazione mirata della sua struttura. I risultati di questo studio, pubblicati su Molecular Cell<\/em>, potrebbero contribuire al progresso nella diagnosi e nel trattamento di alcuni tipi di tumori. <\/p>\n\n\n\n

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FIGURA: illustratoren.de\/TobiasWuestefeld<\/figcaption><\/figure>\n\n\n\n

Il potere e il mistero di MEG3<\/strong><\/h2>\n\n\n\n

Le cellule umane, come quelle di molti altri organismi, hanno sviluppato meccanismi per proteggerci dai tumori. Le cellule sane producono una serie di molecole che impediscono l\u2019accumulo di mutazioni dannose. Il guardiano del genoma pi\u00f9 celebre \u00e8 la proteina p53: ogni volta che p53 diventa inattiva o presenta un malfunzionamento, si verifica un forte aumento del rischio di sviluppare un tumore. MEG3, studiata approfonditamente da Marco Marcia e dal suo gruppo all\u2019EMBL di Grenoble, \u00e8 un\u2019altra molecola prodotta dalle nostre cellule che contribuisce a prevenire i tumori. La sua funzione consiste nello stimolare la proteina p53. Tuttavia, al contrario di p53, MEG3 non \u00e8 una proteina, bens\u00ec appartiene a un gruppo di molecole di RNA scoperte negli ultimi 20 anni chiamate RNA lunghi non codificanti, abbreviato in lncRNA.<\/p>\n\n\n\n

Bench\u00e9 sia probabile che le cellule umane contengano pi\u00f9 lncRNA che proteine, l\u2019importanza biologica e i meccanismi d\u2019azione di queste molecole di RNA restano in gran parte sconosciuti. Alcuni lncRNA, come MEG3, sono legati a malattie. Tuttavia, gli scienziati non sono ancora riusciti a capirne l\u2019esatto funzionamento. Questo ha contribuito a diffondere scetticismo tra alcuni ricercatori del settore. \u201cPoich\u00e9 il funzionamento molecolare dei lncRNA non \u00e8 ancora stato pienamente compreso, molti scienziati continuano a mettere in dubbio l\u2019effettiva rilevanza funzionale di tali molecole\u201d afferma Marcia. <\/p>\n\n\n\n

Perch\u00e9 forma e funzione sono interdipendenti?<\/strong><\/h2>\n\n\n\n

L\u2019obiettivo di Marcia \u00e8 quello di cambiare questa percezione attraverso lo studio della forma tridimensionale dei lncRNA. Insieme al suo gruppo, spera che una conoscenza pi\u00f9 approfondita delle strutture dei lncRNA possa aiutare a comprendere il modo in cui funzionano queste molecole.<\/p>\n\n\n\n

\u201cLe strutture 3D forniscono la mappa molecolare, la cartografia delle molecole biologiche. Quando si visita una nuova citt\u00e0, sapere dove si trovano la stazione ferroviaria, il municipio, le scuole e i parchi \u00e8 importante, poich\u00e9 si tratta degli elementi che contribuiscono al corretto funzionamento della citt\u00e0 stessa. Lo stesso pu\u00f2 dirsi delle biomolecole: \u00e8 importante sapere come \u00e8 ripiegata o organizzata la loro struttura, in modo da poterne identificare le unit\u00e0 funzionali\u201d, sostiene Marcia.<\/p>\n\n\n\n

Grazie alla biochimica, alla biologia cellulare e all\u2019utilizzo di un microscopio a forza atomica a singola particella, il team ha studiato dettagliatamente la struttura della molecola MEG3. Il gruppo ha sistematicamente rimosso e modificato gli elementi costitutivi di MEG3, per scoprire quali sono essenziali alla sua funzionalit\u00e0. In questo modo, i ricercatori hanno identificato due elementi all\u2019interno della molecola pi\u00f9 importanti rispetto ad altri in quanto soppressori tumorali. \u00c8 interessante notare che questi elementi formano strutture a forcina, denominate ‘kissing loop\u2019 dai biologi, che interagiscono tra loro in tre dimensioni.<\/p>\n\n\n\n

Distruggendo questi \u201ckissing loop\u201d attraverso una manipolazione degli elementi costitutivi della molecola MEG3, anche la funzione di soppressore tumorale di MEG3 viene interrotta. Le scoperte dei ricercatori potrebbero avere implicazioni pi\u00f9 ampie. \u201cL\u2019importanza delle strutture 3D dei lncRNA contribuisce a gettare nuova luce su queste molecole\u201d, spiega Marcia. \u201cDimostra infatti che i lncRNA sono molto pi\u00f9 complessi di quanto pensavamo perch\u00e9 devono essere controllati e ripiegati in maniera estremamente precisa per poter funzionare correttamente.\u201d<\/p>\n\n\n\n

Migliorare diagnosi e cura dei tumori al cervello<\/strong><\/h2>\n\n\n\n

Nei mammiferi, la molecola MEG3 \u00e8 largamente diffusa in diversi tessuti, in particolare nel cervello e nelle ghiandole endocrine, come l\u2019ipofisi. I tumori al cervello e all\u2019ipofisi possono svilupparsi quando la molecola MEG3 non funziona correttamente. Finora, l\u2019unico trattamento possibile per queste tipologie di tumori \u00e8 quello chirurgico. Per ovviare alla necessit\u00e0 di ricorrere ad interventi chirurgici invasivi, si potrebbe ricorrere alla stimolazione dell\u2019attivit\u00e0 della molecola MEG3 nel tumore.   <\/p>\n\n\n\n

Creare medicinali che stabilizzino i \u201ckissing loop\u201d della molecola MEG3 potrebbe migliorarne la funzione di soppressore tumorale fino ad arrestare la crescita tumorale. Conoscere la composizione e la struttura della molecola MEG3 sana potrebbe inoltre contribuire all\u2019identificazione di persone con molecole di MEG3 anormalmente ripiegate, che sono quindi pi\u00f9 a rischio di sviluppare un cancro. <\/p>\n\n\n\n

I misteri irrisolti della molecola MEG3 e degli altri lncRNA<\/strong><\/h2>\n\n\n\n

Nonostante il meticoloso lavoro svolto, il gruppo non \u00e8 riuscito a decifrare completamente il mistero che circonda la molecola MEG3. \u201cDobbiamo ancora identificare l\u2019ordine preciso degli eventi che portano all\u2019attivazione e alla stimolazione di p53 da parte di MEG3\u201d, sottolinea Marcia.<\/p>\n\n\n\n

I risultati illustrati in questo nuovo articolo, che vanta anche i contributi di colleghi dell’Institut de Biologie Structurale (laboratorio di biologia strutturale, Grenoble), del dipartimento \u201cCIBIO\u201d (Centro di Biologia Integrata, Universit\u00e0 di Trento) e del Max Delbr\u00fcck Center (centro Max Delbr\u00fcck, Berlino), mostrano la visione molecolare pi\u00f9 dettagliata di un lncRNA finora mai realizzata. Tuttavia, inducono a domandarsi se le strutture 3D siano ugualmente importanti per la funzione di altri lncRNA.  Marcia e il suo gruppo vogliono continuare ad analizzare la struttura e la funzione di altri IncRNA. Tuttavia, da soli non riusciranno mai a studiare le tante migliaia di lncRNA prodotte dalle cellule umane. \u201cSpero davvero che le metodologie e l\u2019approccio sperimentale che abbiamo seguito stimoleranno altri colleghi della comunit\u00e0 scientifica a raccogliere il testimone e aiutarci ad espandere la rappresentazione dei lncRNA\u201d, commenta Marcia<\/p>\n\n\n\n

\n\n\n\n

Los ‘bucles en horquilla’ en una mol\u00e9cula de ARN son esenciales por su papel en la supresi\u00f3n tumoral<\/strong><\/h2>\n\n\n\n

Un equipo de investigadores del grupo Marcia del EMBL de Grenoble, Francia, ha descubierto que el supresor tumoral MEG3 adopta una compleja estructura tridimensional para cumplir su funci\u00f3n. Adem\u00e1s, fueron capaces de afinar su actividad mediante la manipulaci\u00f3n selectiva de esta arquitectura. Los resultados de este estudio, publicados en Molecular Cell<\/em>, podr\u00edan ayudar a avanzar en el diagn\u00f3stico y tratamiento de ciertos tipos de c\u00e1ncer.<\/p>\n\n\n\n

\"\"
ILUSTRACI\u00d3N: illustratoren.de\/TobiasWuestefeld<\/figcaption><\/figure>\n\n\n\n\n\n\n\n

El poder y el misterio de MEG3<\/strong><\/h2>\n\n\n\n

Las c\u00e9lulas humanas, como las de muchos otros organismos, han desarrollado mecanismos para protegernos del c\u00e1ncer. Las c\u00e9lulas sanas producen una serie de mol\u00e9culas que impiden la acumulaci\u00f3n de mutaciones da\u00f1inas. El guardi\u00e1n m\u00e1s famoso de nuestro genoma es la prote\u00edna p53; cuando p53 se vuelve inactiva o funciona mal, el riesgo de desarrollar c\u00e1ncer aumenta dr\u00e1sticamente. MEG3, estudiado en detalle por Marco Marcia y su grupo en el EMBL de Grenoble, es otra mol\u00e9cula de prevenci\u00f3n del c\u00e1ncer que nuestras c\u00e9lulas producen. Su funci\u00f3n consiste en la estimulaci\u00f3n de p53. Sin embargo, a diferencia de p53, MEG3 no es una prote\u00edna, sino que pertenece a una clase de mol\u00e9culas de ARN descubiertas en los \u00faltimos 20 a\u00f1os, llamadas ARNs largos no codificantes: ARNlnc para abreviar.<\/p>\n\n\n\n

Mientras que las c\u00e9lulas humanas probablemente contienen m\u00e1s ARNlnc que prote\u00ednas, la importancia biol\u00f3gica y los mecanismos de acci\u00f3n de estos ARNs siguen siendo un misterio. Algunos ARNlnc, como MEG3, est\u00e1n relacionados con enfermedades, pero los cient\u00edficos no han sido capaces de descifrar c\u00f3mo funcionan exactamente. Esto ha provocado escepticismo entre algunos investigadores en el campo, dice Marcia. \u201cDebido a la falta de comprensi\u00f3n de c\u00f3mo funcionan los ARNlnc a nivel molecular, muchos cient\u00edficos todav\u00eda cuestionan la relevancia funcional real de estas mol\u00e9culas.\u201d<\/p>\n\n\n\n

Por qu\u00e9 la forma y la funci\u00f3n est\u00e1n interrelacionadas<\/strong><\/h2>\n\n\n\n

El objetivo de Marcia era cambiar esta percepci\u00f3n y estudiar la forma tridimensional de los ARNlnc. Junto a su equipo, esperan que al profundizar m\u00e1s en las estructuras del ARNlnc, se llegue a comprender mejor c\u00f3mo funcionan estas mol\u00e9culas.<\/p>\n\n\n\n

\u201cLas estructuras 3D proporcionan el mapa molecular, la cartograf\u00eda molecular de las mol\u00e9culas biol\u00f3gicas. Cuando se visita una nueva ciudad, se quiere saber d\u00f3nde est\u00e1 la estaci\u00f3n de ferrocarril, el ayuntamiento, las escuelas, los parques, porque \u00e9sos son los elementos que hacen funcionar la ciudad correctamente. Lo mismo ocurre con las biomol\u00e9culas: se necesita saber c\u00f3mo est\u00e1n plegadas y estructuradas para poder identificar sus unidades funcionales\u201d, dice Marcia.<\/p>\n\n\n\n

Mediante la bioqu\u00edmica, la biolog\u00eda celular y la microscop\u00eda de fuerza at\u00f3mica de part\u00edculas individuales, el equipo estudi\u00f3 la estructura de MEG3 con gran detalle. Eliminaron y modificaron sistem\u00e1ticamente los bloques de construcci\u00f3n de MEG3 para averiguar cu\u00e1les de ellos eran esenciales en su funcionalidad. De esta manera, los investigadores descubrieron dos elementos dentro de la mol\u00e9cula que eran m\u00e1s importantes para su funci\u00f3n como supresor tumoral que otros. Curiosamente, estos elementos forman estructuras de horquilla, lo que los bi\u00f3logos llaman \u201cbucles en horquilla\u201d, y que interact\u00faan entre s\u00ed en tres dimensiones.<\/p>\n\n\n\n

Cuando se alteraron estos bucles en horquilla por la manipulaci\u00f3n de los elementos constitutivos de MEG3, la funci\u00f3n de supresi\u00f3n tumoral de MEG3 tambi\u00e9n se vio interrumpida. Los hallazgos de los investigadores podr\u00edan tener implicaciones m\u00e1s amplias, como explica Marcia: \u201cEl hecho de que la estructura tridimensional de los ARNlnc sea tan importante arroja nueva luz sobre estas mol\u00e9culas. Demuestra que las mol\u00e9culas de ARNlnc son mucho m\u00e1s sofisticadas de lo que pens\u00e1bamos, porque necesitan estar controladas y plegadas con mucha precisi\u00f3n para funcionar correctamente.\u201d<\/p>\n\n\n\n

Mejorar el diagn\u00f3stico y el tratamiento del c\u00e1ncer cerebral<\/strong><\/h2>\n\n\n\n

MEG3 abunda en diferentes tejidos de mam\u00edferos, particularmente en el cerebro y las gl\u00e1ndulas endocrinas, como la gl\u00e1ndula pituitaria. Los tumores en el cerebro y la gl\u00e1ndula pituitaria se pueden desarrollar cuando MEG3 no est\u00e1 funcionando adecuadamente. Hasta la fecha, este tipo de tumores s\u00f3lo pueden tratarse mediante cirug\u00eda. Una forma de superar la necesidad de la cirug\u00eda invasiva ser\u00eda estimular la actividad de MEG3 en el tumor.<\/p>\n\n\n\n

El dise\u00f1o de f\u00e1rmacos que estabilicen los bucles en horquilla de MEG3 podr\u00eda mejorar su funci\u00f3n supresora tumoral hasta el punto de poder detener el crecimiento tumoral. El conocimiento sobre la composici\u00f3n de MEG3 saludable tambi\u00e9n podr\u00eda ayudar a identificar a las personas con MEG3 anormalmente plegado y, por lo tanto, con mayor riesgo de desarrollar un c\u00e1ncer.<\/p>\n\n\n\n

Los misterios sin resolver en torno a MEG3 y otros ARNlnc<\/strong><\/h2>\n\n\n\n

A pesar de su meticuloso trabajo, el equipo no ha resuelto a\u00fan todo el rompecabezas que rodea a MEG3, como subraya Marcia: \u201cTodav\u00eda tenemos que descubrir el orden preciso de los acontecimientos que conducen a la activaci\u00f3n y a la estimulaci\u00f3n de p53 por parte de MEG3.\u201d<\/p>\n\n\n\n

Los resultados proporcionados en este nuevo art\u00edculo, que tambi\u00e9n incluye contribuciones de colegas del Institut de Biologie Structurale (Grenoble), del Departamento CIBIO (Universidad de Trento) y del Max Delbr\u00fcck Center (Berl\u00edn), presentan la visi\u00f3n molecular m\u00e1s detallada de un ARNlnc hasta la fecha, pero suscitan la pregunta de si las estructuras 3D son igualmente importantes para la funci\u00f3n de otros ARNlnc. El equipo de Marcia quiere seguir analizando la estructura y la funci\u00f3n de otros ARNlnc. Sin embargo, les ser\u00e1 imposible por s\u00ed solos estudiar los tantos miles de ARNlnc que producen las c\u00e9lulas humanas. \u00abEspero de verdad que los m\u00e9todos y el enfoque experimental que hemos seguido estimulen a otros colegas de la comunidad para tomar el relevo de nuestro estudio, y que as\u00ed nos ayuden a expandir la caracterizaci\u00f3n de los ARNlnc\u00bb, dice Marcia.<\/p>\n","protected":false},"excerpt":{"rendered":"

MEG3 adopts a complex three-dimensional structure to fulfil its tumour suppressor function.<\/p>\n","protected":false},"author":70,"featured_media":17122,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[2,17591],"tags":[37,907,547,909,908,1748,70],"embl_taxonomy":[],"class_list":["post-17098","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","category-science-technology","tag-grenoble","tag-lncrna","tag-marcia","tag-meg3","tag-p54","tag-press-release","tag-rna"],"acf":{"article_intro":"","related_links":[{"link_description":"","link_url":""},{"link_description":"","link_url":""}],"article_sources":[{"source_description":"

Tina Uroda, Eleni Anastasakou, Annalisa Rossi, Jean-Marie Teulon, Jean-Luc Pellequer, Paolo Annibale, Ombeline Pessey, Alberto Inga, Isabel Chillon, Marco Marcia: Conserved pseudoknots in lncRNA MEG3 are essential for stimulation of the p53 pathway. Molecular Cell, published on 20 August 2019.<\/p>\n","source_link_url":"https:\/\/www.cell.com\/molecular-cell\/fulltext\/S1097-2765(19)30563-5"}],"vf_locked":false,"featured":false,"color":"#007B53","show_featured_image":false,"in_this_article":false,"youtube_url":"","mp4_url":"","video_caption":"","press_contact":"EMBL Generic","field_target_display":"embl","source_article":false},"embl_taxonomy_terms":[],"yoast_head":"\nMEG3 kissing loops essential for tumour suppression | EMBL<\/title>\n<meta name=\"description\" content=\"EMBL scientists have found that MEG3 adopts a 3D structure to fulfil its function. These results might help to advance diagnosis and treatment of cancer.\u00a0\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.embl.org\/news\/science\/kissing-loops-in-lncrna\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"MEG3 kissing loops essential for tumour suppression | EMBL\" \/>\n<meta property=\"og:description\" content=\"EMBL scientists have found that MEG3 adopts a 3D structure to fulfil its function. 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