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Role of Dcps in Mammalian RNA Regulation and Human Diseases

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Role of Dcps in Mammalian RNA Regulation and Human Diseases ROLE OF DCPS IN MAMMALIAN RNA REGULATION AND HUMAN DISEASES By MI ZHOU A dissertation submitted to the Graduate School-New Brunswick and The Graduate School of Biomedical Sciences Rutgers, The State University of New Jersey In partial fulfillment of the requirements For the degree of Doctor of Philosophy Graduate Program in Cell and Development Biology Written under the direction of Dr. Megerditch Kiledjian And approved by _________________________________ _________________________________ _________________________________ _________________________________ New Brunswick, New Jersey October, 2015 ABSTRACT OF THE DISSERTATION Role of DcpS in Mammalian RNA Regulation and Human Diseases By MI ZHOU Dissertation Director Dr. Megerditch Kiledjian In eukaryotic cells, mRNA degradation plays an important role in the control of gene expression and is therefore highly regulated. The scavenger decapping enzyme DcpS is a multifunctional protein that plays a critical role in mRNA degradation. We first sought to identify DcpS target genes in mammalian cells using a cell permeable DcpS inhibitor compound, RG3039, which was initially developed for therapeutic treatment of Spinal Muscular Atrophy (SMA). Microarray analysis following DcpS decapping inhibition by RG3039 revealed the steady state levels of 222 RNAs were altered. Of a subset selected for validation by qRT-PCR, two non-coding transcripts dependent on DcpS decapping activity, were identified and referred to as DcpS Responsive Noncoding Transcript (DRNT) 1 and 2 respectively. Only the increase in DRNT1 transcript was accompanied with an increase of its RNA stability and this increase was dependent on both DcpS and Xrn1. Our data indicate that DcpS is a transcript-restricted modulator of RNA stability in mammalian cells and the RG3039 ii quinazoline compound is pleotropic, influence gene expression in both an apparent DcpS dependent and independent manner. A surprising development was uncovered in a collaborative study where two distinct mutations in the DcpS gene (c.636+1G>A, DcpSIns15 and c.947C>T, DcpST316M) were identified as the underlying cause of autosomal recessive intellectual disability within a consanguineous family. Both of the mutations were confirmed to disrupt DcpS decapping activity in vitro and/or in vivo, indicating that the decapping activity of DcpS is critical for normal neurological development. Consistent with a role for DcpS in neuronal cells, our studies with the DcpSIns15 variant uncovered a link between this variant DcpS and Spinal Muscular Atrophy (SMA). Exogenous expression of DcpSIns15 in SMA patient fibroblast cells increased SMN2 mRNA and corresponding SMN protein levels. Our findings suggest that strategies to shift wild type DcpS splicing patterns to partially yield the variant DcpS Ins15 splicing pattern may be beneficial for SMA therapeutics. iii ACKNOWLEGEMENT I would like to thank my advisor, Dr. Mike Kiledjian for all of his guidance, support and advice during the past four years. I appreciate all his contributions of time, ideas, and funding to make my PhD experience productive and stimulating. I am so grateful for his guidance on both academic and life, including independent thinking ability, the writing and presentation skills, as well as personal and communication skills. His encouragement and unwavering support has sustained me through frustration and depression. Without his pushing me ahead, the completion of my PhD study would be impossible. I would like to thank the members of my thesis committee, Dr. Lori Covey, Dr. Sam Gunderson, Dr. Paul Copeland for their advice and suggestions during my PhD study as well as sharing facilities and reagents and providing indispensable help to my research work. I would like to thank our collaborators Dr John B. Vincent from University of Toronto (Canada) and Dr Rami Abou Jamra from Friedrich-Alexander University (Germany). They discovered the family with Intellectual Disability patients from remote Pakistan area and identified the critical mutations in DcpS by genomic sequencing analysis. Their genius work was the foundation for my project of DcpS in Intellectual Disability and SMA. I would like to thank the current and past members of the lab, Xinfu Jiao, Ewa Grudzien, Xiaobin Luo, Huijuan Cui, Mangen Song, and Madel Durens, for their support, help and friendship in the past four years. I would especially like to thank Xinfu for his iv technical support and generous contribution of time in helping me with research experiments throughout my PhD study. Last and most importantly, I would like to thank my family for the support they provided me through my entire life. In particular, I must acknowledge my husband and also a former lab member, You Li, for his support, tolerance, patience and love in work and life. v TABLE OF CONTENTS ABSTRACT OF THE DISSERTATION ........................................................................... ii ACKNOWLEGEMENT .................................................................................................... iv TABLE OF CONTENTS ................................................................................................... vi LIST OF TABLES ............................................................................................................. ix LIST OF FIGURES ............................................................................................................ x Introduction ......................................................................................................................... 1 General mRNA Degradation ........................................................................................... 1 5′ Decapping enzymes ................................................................................................ 2 Xrn1 exonuclease ........................................................................................................ 3 Exosome exonuclease complex .................................................................................. 5 The Scavenger Decapping Enzyme DcpS ...................................................................... 6 pre-mRNA Splicing and Regulation ............................................................................... 8 Translation .................................................................................................................... 11 Cap-dependent Translation Initiation ....................................................................... 11 Cap-independent translation initiation by IRES ....................................................... 13 Spinal Muscular Atrophy .............................................................................................. 14 SMN complex ........................................................................................................... 14 SMA .......................................................................................................................... 15 vi C5-quinazoline compounds in SMA therapeutic application ................................... 17 Intellectual Disability .................................................................................................... 19 Materials and Methods ...................................................................................................... 22 Plasmid constructs ........................................................................................................ 22 His-tag protein purification ........................................................................................... 23 Cell culture and transfections........................................................................................ 24 Lentiviral production and infection .............................................................................. 25 RNA isolation, reverse transcription and Real time PCR ............................................. 26 Microarray ..................................................................................................................... 26 Western Blotting ........................................................................................................... 26 Immunofluorescence ..................................................................................................... 27 RACE and DNA gel electrophoresis ............................................................................ 27 Generation of labeled RNA and cap structures ............................................................. 28 Electrophoretic mobility shift assays ............................................................................ 28 In vitro decapping assays .............................................................................................. 29 Dicistronic reporter assay ............................................................................................. 29 Generation of RNA in vitro .......................................................................................... 30 In vitro translation ......................................................................................................... 30 Chapter I DcpS is a Transcript Specific Modulator of RNA in Mammalian Cells .......... 34 Summary ....................................................................................................................... 34 vii Introduction ................................................................................................................... 35 Results ..........................................................................................................................
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