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The Role of DIS3L2 in the Degradation of the Uridylated RNA Species in Humans

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The Role of DIS3L2 in the Degradation of the Uridylated RNA Species in Humans MASARYK UNIVERSITY Faculty of Science National Center for Biomedical Research Dmytro Ustianenko The role of DIS3L2 in the degradation of the uridylated RNA species in humans Ph.D. THESIS SUPERVISOR doc. Mgr. ŠTĚPÁNKA VAŇÁČOVÁ, Ph.D. BRNO, 2014 _______________________________ Cover: A schematic representation of the RNA degradation process which oc- curs in the cytoplasm. Copyright © 2014 Dmytro Ustianenko, Masaryk University, All rights reserved. _______________________________ Copyright © Dmytro Ustianenko, Masaryk University Bibliographic entry Author: Mgr. Dmytro Ustianenko Faculty of Science, Masaryk University National Centre for Biomolecular Research Central European Institute of Technology Title of Dissertation: The role of DIS3L2 in the degradation of the uridylat- ed RNA species in humans. Degree Programme: Biochemistry Field of Study: Biomolecular chemistry Supervisor: Doc. Mgr. Štěpánka Vaňáčová, Ph.D. Academic Year: 2014 Number of Pages: 131 Keywords: RNA degradation, DIS3L2, uridylation, humans, miRNA, let-7 Bibliografický záznam Autor: Mgr. Dmytro Ustianenko Přírodovědecká fakulta, Masarykova univerzita Národní centrum pro výzkum biomolekul Středoevropský technologický institut Název práce: The role of DIS3L2 in the degradation of the uridylat- ed RNA species in humans. Studijní program: Biochemie Studijní obor: Biomolekulární chemie Školitel: doc. Mgr. Štěpánka Vaňáčová, Ph.D. Akademický rok: 2014 Počet stran: 131 Klíčová slova: RNA degradace, DIS3L2, uridylace, mikro RNA, let-7 Acknowledgements I would like to thank to all the people who have contributed to this work. Foremost I would like to thank my supervisor Stepanka Vanacova for her enthusiasm, support and patience though all of my studies. I would like to acknowledge the members of the RNA processing and degradation group for their support and help in achieving this goal. Besides, I would like to thank to all those people who were standing next by me for all this long years. Those who were supporting me, loved me and inspired me. Those who have not gave up on me, those who gave me energy and courage to go on. Without you this work would be impossible to accomplish. To those who died defendending Ukrainian independence in winter 2014 Подяка Я хочу подякувати всім хто сприяв цій роботі. Перш за все я хочу подякувати моєму керівнику Степанце Ванячовій за її ентузіазм, підтримку та терпіння протягом мого навчання. Також хочу подякувати всім членам моєї лабораторії за їх підтримку в досягненні мети. Особливо хочу відзначити всіх хто був поруч зі мною всі ці довгі роки. Тим хто підтримував мене, кохав та надихав. Тим хто не зрадив, тим хто давав натхнення та сили йти далі. Без вас це було б не можливо. Тим хто загинув захищаючи незалежність України зимою 2014 року В целях природы обуздания, В целях рассеять неученья Тьму Берём картину мироздания – да! И тупо смотрим, что к чему… Братья Стругацкие, “Понедельник начинается в субботу” Abstract The process of the RNA decay is an essential mechanism required for the function and maintenance of the cell homeostasis. It is closely connected with the RNA processing, metabolism and quality control. Here I character- ized both in vivo and in vitro the Perlman syndrome associated human 3' to 5' exonuclease DIS3L2. I report that unlike its other human homologs, DIS3L2 is acting independently of the core exosome complex in the cytoplasm of human cells. I show that DIS3L2 is involved in targeting uridylated species of the pre-miRNA from the let-7 family which play a critical role during the cell differentiation. Besides this, I report on a novel repertoire of the RNA substrates which are targeted by DIS3L2. I show that DIS3L2 mediated RNA degradation is triggered by the 3' end uridylation of the RNA in vivo. We show that various classes of the RNA can be uridylated and recognized by DIS3L2. These include mRNAs, snRNAs, miRNA’s and previously unreported uridylat- ed tRNA’s. Suggesting, that exonuclease DIS3L2 is an essential component of the RNA turnover and potential processing. Abstrakt Process degradace RNA představuje mechanismus nezbytný pro funk- ci a udržení vnitřní rovnováhy buněk. Tento proces je spojen s procesováním, metabolismem a kontrolou kvality RNA. V této části práce charakterizujeme in vivo a in vitro lidskou 3' - 5' exonukleáza u DIS3L2, která je spojena s tzv. Perlmanovým syndromem. Narozdíl od ostatních lidských homologních proteinů, DIS3L2 funguje nezávisle na jádru exosomu v cytoplazmě lidských buněk. Ukazujeme zde také, že DIS3L2 je zahrnuta v rozpoznávání uridylo- vaných typů pre-mRNA z rodiny let-7, která hraje důležitou roli během difer- enciace lidských buněk. Kromě toho bylo identifikováno nové spektrum RNA molekul, které reprezentují cílovou skupinu proteinu DIS3L2. Ukazujeme, že zcela nová skupina molekul RNA může být rozpoznána a uridylována pro- teinem DIS3L2. Tato skupina zahrnuje mRNA, snRNA miRNA a uridylované molekuly tRNA, které nebyly zatím publikovány. Výsledky ukazují, ze exo- nukleáza DIS3L2 představuje nezbytný prvek v metabolismu a procesování RNA. Table of contents Bibliographic entry ....................................................................... 7 Bibliografický záznam .................................................................. 9 Acknowledgements ...................................................................... 11 Подяка ........................................................................................... 11 Abstract ......................................................................................... 15 Abstrakt ......................................................................................... 17 Table of contents .......................................................................... 19 Introduction ................................................................................... 23 Nuclear RNA quality control machinery ..................................... 23 Noncanonical polymerases in human ........................................ 25 Mechanisms of the UTP specificity of terminal uridyl transferases ..................................................................... 28 Uridylation of mammalian RNAs ................................................. 30 The role of the uridylation in histone mRNA degradation .......... 31 The role of uridylation in miRNA processing and degradation ... 32 Uridylation of the miRNA............................................................ 35 RNA degradation at the 3' ends .................................................. 38 Exosome complex in eukaryotes ............................................... 38 DIS3 homologs in humans......................................................... 40 Human DIS3 Like exonuclease 2 .............................................. 41 Other known 3' to 5' exonucleases ............................................ 42 Genome-wide approaches to study protein-RNA interactions 43 References ................................................................................ 46 Mammalian DIS3L2 exoribonuclease targets the uridylated precursors of let-7 miRNA’s. ................. 64 Supplementary data................................................................... 74 DIS3L2 is involved in the degradation of the uridylated tRNA fragments .................................................... 84 Abstract...................................................................................... 85 Introduction ................................................................................ 86 Results ....................................................................................... 89 Identification of DIS3L2 RNA targets by PAR-CLIP ................... 89 DIS3L2 predominantly crosslinks to tRNA 5' ends .................... 92 DIS3L2 and 5' tRFs associate with active polysomes ............... 95 TUTase 4 uridylates 5’ tRF’s ...................................................... 99 Discussion ................................................................................. 101 Material and Methods ................................................................ 105 Summary ....................................................................................... 124 Curriculum vitae ........................................................................... 126 List of conferences....................................................................... 129 List of publications ....................................................................... 130 Dmytro Ustianenko Introduction Introduction Nuclear RNA quality control machinery The processes of the RNA degradation, turnover and quality control are absolutely essential for the survival and homeostasis of the eukaryotic cell. Each step of the RNA metabolism is tightly controlled by the quality control machinery to ensure the immediate recognition and removal of the aberrant molecule from the cell. This process is crucial as the presence of misfunc- tional RNAs could lead to the severe disbalance of the cell or even whole organism. Eukaryotes have evolved several mechanisms to monitor RNA pro- cessing, maturation as well as proper functioning of the RNA though so called quality control mechanisms. This occurs in both nucleus and cytoplasm of the cell. In the cytoplasm, nonsense-mediated mRNA decay is targeting the mRNA’s that possesses the prematurely located stop codon. It is important for cells to eliminate mRNAs that prematurely terminate translation since the resulting truncated proteins have the potential to be nonfunctional or
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