50 and 30 modifications controlling RNA

degradation: from safeguards to

rstb.royalsocietypublishing.org executioners
Dominique Gagliardi1 and Andrzej Dziembowski2,3
1
Institut de biologie moléculaire des plantes (IBMP), Centre national de la recherche scientifique (CNRS),
Introduction Université de Strasbourg, 12 rue Zimmer, 67000 Strasbourg, France
2
Laboratory of RNA Biology and Functional Genomics, Institute of Biochemistry and Biophysics,
Cite this article: Gagliardi D, Dziembowski A. Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
2018 50 and 30 modifications controlling RNA 3
Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106
degradation: from safeguards to executioners. Warsaw, Poland
Phil. Trans. R. Soc. B 373: 20180160. DG, 0000-0002-5871-7544
http://dx.doi.org/10.1098/rstb.2018.0160
RNA degradation is a key process in the regulation of gene expression. In all
organisms, RNA degradation participates in controlling coding and non-
Accepted: 5 October 2018 coding RNA levels in response to developmental and environmental cues.
RNA degradation is also crucial for the elimination of defective RNAs.
One contribution of 11 to a theme issue ‘50 Those defective RNAs are mostly produced by ‘mistakes’ made by the RNA
and 30 modifications controlling RNA processing machinery during the maturation of functional transcripts from
their precursors. The constant control of RNA quality prevents potential dele-
degradation’.
terious effects caused by the accumulation of aberrant non-coding transcripts
or by the translation of defective messenger RNAs (mRNAs). Prokaryotic
Subject Areas: and eukaryotic organisms are also under the constant threat of attacks from
molecular biology pathogens, mostly viruses, and one common line of defence involves the ribo-
nucleolytic digestion of the invader’s RNA. Finally, mutations in components
involved in RNA degradation are associated with numerous diseases in
Keywords: humans, and this together with the multiplicity of its roles illustrates the bio-
RNA modifications, RNA degradation, m7G cap, logical importance of RNA degradation. RNA degradation is mostly viewed
poly(A) tail, polyadenylation, uridylation as a default pathway: any functional RNA (including a successful pathogenic
RNA) must be protected from the scavenging RNA degradation machinery.
Yet, this protection must be temporary, and it will be overcome at one point
Authors for correspondence:
because the ultimate fate of any cellular RNA is to be eliminated. This special
Dominique Gagliardi issue focuses on modifications deposited at the 50 or the 30 extremities of RNA,
e-mail: dominique.gagliardi@ibmp-cnrs. and how these modifications control RNA stability or degradation.
unistra.fr This article is part of the theme issue ‘50 and 30 modifications controlling
Andrzej Dziembowski RNA degradation’.
e-mail: [email protected]

1. Introduction
The expression of genetic information is tightly regulated in all cells. In eukar-
yotes, this is a very complex process regulated at multiple levels from chromatin
structure and transcription initiation, elongation and termination to pre-RNA
processing, RNA localization and decay. Additional layers of regulation operate
at the translational and post-translational levels.
Transcription produces both non-coding RNAs and messenger RNAs
(mRNAs). Eukaryotic mature mRNA molecules are generated through mostly
co-transcriptional processing reactions [1]. In the early stage of transcription,
the 50 end of mRNA is modified by a so-called m7G cap structure formed by
7-methylguanylate connected to mRNA via an unusual 50 to 50 triphosphate
linkage [2]. Additional internal chemical modifications of nucleotides occur
during mRNA biogenesis, such as the methylation of adenosines at position
6 (m6A) [3]. The exhaustive identification of the nature, extent and functions
of all modifications targeting mRNAs currently constitutes a very dynamic
and exciting field of investigations [4]. The body of the pre-messenger RNA

& 2018 The Author(s) Published by the Royal Society. All rights reserved.
is also spliced to remove introns [5], which in some organ- mature miRNAs or nuclear non-coding RNAs. Such modifi- 2
isms constitute the predominant part of pre-mRNA cations can stabilize RNA molecules or induce their decay.

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molecules. Finally, 30 -end processing generates a mature 30 Of note, the destabilization of RNA by nucleotide tailing is a
terminus, which is polyadenylated by canonical poly(A) conserved process across organisms and it was identified in
polymerases (ncPAPs) [6]. The only eukaryotic mRNAs Escherichia coli [27]. Although in bacteria, bulk RNA decay is
whose 30 end processing does not involve polyadenylation initiated by endonucleolytic events, the ends of RNA molecules
are the replication-dependant histone mRNAs in mammals also play an important role in controlling RNA fate. Secondary
[7]. Those particular mRNAs contain an RNA stem-loop structures may impede the progression of 30 to 50 exoribonu-
structure close to the 30 end of the mature RNA and are cleases and polyadenylation accelerates the degradation of
processed by a specific mechanism. In addition to producing RNA decay intermediates facilitating the action of 30 to 50 exo-
pre-mRNA, independent transcription units produce precur- ribonucleases. Moreover, the triphosphate moiety present at the
sors of several other functional RNA classes (e.g. pre-rRNA, 50 end of the primary transcripts restricts endonucleolytic clea-

Phil. Trans. R. Soc. B 373: 20180160

pre-snRNA, pre-miRNA), as well as pervasive transcripts vage by the RNase E and its conversion to monophosphate
such as long intergenic non-coding RNAs, many of which accelerates the decay rates of many, but not all, transcripts [28].
play important regulatory roles [8]. Such RNAs are processed Because of the impact of the ends of RNA molecules on
by a variety of different mechanisms. their stability and biological functions, all RNA modifications
Although the decay of eukaryotic RNAs can be initiated by must be tightly controlled, and complex regulatory networks
endoribonucleolytic cleavages, it is mainly carried out by exo- of protein–protein and protein–RNA interactions are involved
ribonucleases [9]. Therefore, 50 and 30 ends of RNA molecules in capping/decapping, polyadenylation/deadenylation and
need to be protected. In the case of non-coding RNAs, this uridylation. This field of research is currently expanding, and
protection is mostly achieved by shielding 50 and 30 extremities several key discoveries were made in recent years. This
within the ribonucleoparticle, which is formed by the non- theme issue of Philosophical Transactions B entitled ‘50 and
coding RNA and its associated proteins. A diversity of 30 modifications controlling RNA degradation’ gathers articles
processes can also contribute to the protection of extremities explaining how 50 and 30 RNA modifications control the decay
of non-coding RNAs. For instance, 2-O’-methylation of the of coding and non-coding RNAs. The first three articles focus
last 30 nucleotide stabilizes all small RNAs in plants [10,11] on the cap structure, followed by seven articles about various
and piRNAs in animals [12]. In the case of mRNA, the 50 aspects of RNA tailing by non-canonical poly(A) polymerases
end is blocked by the m7G cap structure while the 30 end con- and TUTases.
tains a poly(A) tail. Nucleotides adjacent to the m7G cap can Charenton et al. [29] describe how the removal of the 50
be further methylated to either stabilize transcripts or increase end cap structure is regulated, focusing on the mechanistic
translation of certain mRNAs [13]. The m7G cap initially is aspect. Although the elimination of the mRNA m7GpppN
recognized by the nuclear cap binding complex, which facili- cap is a simple chemical reaction catalysed by the Nudix
tates mRNA export from the nucleus and is later replaced by family hydrolase Dcp2, this enzyme has intrinsically very
the essential translation initiation factor, eIF4E. Interestingly, weak activity [30]. Thus, it requires several accessory factors
in addition to the classical m7G cap, a new type of cap, the that enhance its activity. In recent years, there has been
nicotinamide adenine dinucleotide (NADþ) cap was recently considerable progress in our understanding of how all these
identified in bacteria, yeast and humans [14,15]. In yeast and proteins such as Dcp1, Lsm1–7 complexes, Pat1, Edc1–
humans, about 1–5% of mRNAs contain NADþ rather than Edc2 and/or Edc3 cooperate with Dcp2 to ensure that
m7G cap. In contrast to m7G cap, the NADþ cap cannot removal of the mRNA cap structure is tightly controlled.
support translation in human cells and destabilizes mRNAs Toczydlowska-Socha et al. [31] describe RNA helicase
through the deNADding activity of the DXO proteins [16]. DDX15 as a novel regulator of cap methylation. In contrast
The discovery of alternative caps and the elucidation of their to yeast, the vertebrate m7GpppN cap can be post-transcrip-
function are certainly exciting areas of research. tionally modified at the first nucleotide by RNA cap1
At the other end of the mRNA, the poly(A) tail is bound by methyltransferase (CMTr1) [32,33]. Such modification is
poly(A) binding proteins (PABPs), which facilitate mRNA believed to play a role in antiviral defence [34]. Very little is
export from the nucleus and enhance protein synthesis through known about the regulation of CMTr1-mediated cap modifi-
interactions with translation initiation factors [17]. Poly(A) also cation. The authors identified RNA helicase DHX15 as a
stabilizes mRNA molecules by preventing exoribonucleolytic CMTr1 interactor. They further show that CMTr1 activity is
decay. Consequently, the deadenylation rate largely determines hindered towards RNA substrates with highly structured 50 -
mRNA half-life. Shortening a poly(A) tail in the cytoplasm to termini and DHX15 facilitates methylation of such RNA
fewer than 15–20 nt destabilizes its interaction with the last species. The physiological role of this effect remains to be
PABP [18,19]. Once this last PABP is released, the mRNA established, but this article describes the first example of
becomes translationally inactive and susceptible to degradation, regulated 2’-O-ribose methylation of the mRNA cap structure.
either through the decapping and 50 to 30 decay or by 30 to 50 Because of the importance of the cap structure for mRNA
decay pathway. However, it is now appreciated that poly(A) stability and protein synthesis, there is a clear need for the
tail dynamics is more complex than previously suspected. development of novel tools for the analysis of mRNA cap
Deadenylated mRNAs can be uridylated [20–22] or stored in metabolism [35]. Bednarek et al. [36] invented several novel
a dormant state to be later re-adenylated to activate protein biotin-labelled cap analogues modified within the tripho-
synthesis [23–26]. Such reactions are mediated by terminal sphate bridge to increase their stability in cellular
uridylyltransferases (TUTases) and non-canonical poly(A) conditions. They are efficiently incorporated into RNA
polymerases. Interestingly, the non-canonical addition of non- in vitro and can be applied to a variety of different exper-
templated nucleotides is important for the physiology of not iments including protein affinity purification, pull-down
only mRNAs but also other RNA classes such as pre-miRNAs, assays, in vivo visualization, cellular delivery, etc.
 The first contribution of the seven articles that focus on substrates include nuclear and cytosolic RNAs, coding and 3
the tailing of RNA 30 ends is by Hajnsdorf and Kaberdin non-coding, and also viral RNAs. The different roles of

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[37], who describe how oligoadenylation facilitates RNA RNA uridylation are then explained. This description is not
decay in bacteria. Hajnsdorf and Kaberdin present the restricted to various degradative mechanisms but also
machinery responsible for the oligoadenylation of bacterial includes the role of uridylation in promoting maturation,
RNAs and their degradation. They focus mostly on the and possibly controlling localization or translation.
knowledge obtained in E. coli, because the seminal discov- De Almeida, Scheer et al. [46] focus on RNA uridylation in
eries in this field were made using this model organism. plants. The uridylation of various RNA substrates has been
Yet, work performed on evolutionarily distant bacteria is investigated in plants, from small RNAs and other non-
also mentioned. Hajnsdorf and Kaberdin summarize the coding RNAs, to mRNAs. Most of the knowledge on plant
known RNA targets of oligoadenylation in E. coli to define RNA uridylation was obtained using the flowering plant Arabi-
the impact of oligoadenylation on gene expression. dopsis thaliana, but seminal work was also done in the green

Phil. Trans. R. Soc. B 373: 20180160

By reading the following review by Tudek et al. [38], an algae Chlamydomonas reinhardtii. Both forward and reverse gen-
interesting comparison can be made between the complexity etic strategies led to the identification of two distinctive
of roles played by oligo/polyadenylation in bacteria versus TUTases in these model plant species: MUT68/HESO1 and
eukaryotes. Tudek et al. focus on the intricate role of URT1. De Almeida, Scheer et al. report a detailed evolutionary
poly(A) tails in controlling RNA fate in the nucleus of bud- history of both TUTases in Archaeplastida (i.e. all plants).
ding yeast and human cells. Although polyadenylation of HESO1 and URT1 homologues each form a monophyletic
eukaryotic mRNAs is known to promote stability, export group, and the presence of both TUTases has been maintained
from the nucleus and translation, oligoadenylation also oper- in almost all species of the green lineage, indicating specific and
ates as an RNA destabilizing tag in eukaryotic nuclei. This critical functions. De Almeida, Scheer et al. then recapitulate the
RNA destabilizing role of oligoadenylation is therefore con- diverse molecular functions of both TUTases during RNA
served across evolution, from bacteria to man, and it degradation processes in plants and conclude with key points
actually represents the primordial role of oligoadenylation. of future research.
Tudek et al. provide a detailed view of the different mechan- The article by Meaux and co-authors [47] combines a
isms and factors leading to the polyadenylation of eukaryotic review of our current knowledge on how uridylation induces
RNAs. One could think that the distinction between the pro- decay of replication-dependent histone mRNAs in mammals,
cesses leading to destabilization or stabilization by with new information on two molecular players involved in
polyadenylation is straightforward. On the contrary, Tudek this process: the serine/threonine protein kinase Smg1 and
et al. demonstrate that this boundary is becoming increas- the RNA helicase Upf1. Replication-dependent histone
ingly uncertain, with both pathways sharing common factors. mRNAs in mammals are the only mRNAs that are not poly-
The next review article is by Warkocki et al. [39], who adenylated. Instead of a poly(A) tail, they end with a short
summarizes our current knowledge about all mammalian stem-loop structure. The levels of those mRNAs are tightly
ncPAPs and TUTases. Previously, 7 ncPAPs and TUTases regulated, with a massive degradation at the end of the
have been annotated in the human genome. Recently, a new S-phase or in response to inhibition of DNA synthesis. This
TENT5 (FAM46) family of four members has been identified degradation involves uridylation and, besides TUTases,
[40,41]. Thus, the human genome encodes at least 11 ncPAPs key factors like the stem-loop binding protein (SLBP) or the
and TUTases. Our knowledge about these enzymes is very frag- exoribonuclease, 30 hExo (ERI1). Meaux et al. bring new infor-
mentary and in many cases there are conflicting reports about mation on the involvement of Upf1 domains in this process
their substrate specificity. Nonetheless, it is an exciting field of and report that the kinase Smg1 is required for histone
investigation and several recent reports indicate that they have mRNA degradation when DNA replication is inhibited. In
important, although diverse, physiological roles. For instance, addition, they show by using a strategy based on high-
uridylation by TUT7/TUT4 in the cytoplasm induces decay of throughput sequencing, that the pathway of rapid histone
various RNA species and protects cells against viruses and mRNA degradation is identical at the end of S-phase or
LINE-1 retrotransposons. Nuclear TUTase (TUT1) is involved when DNA replication is inhibited in S-phase.
in U6 snRNA 30 end formation [42] and was also suggested to The final article in this issue by Ugolini and Halic [48]
polyadenylate a subset of mRNAs in a phosphatidylinositol gives an overview of the mechanisms of RNA-based defence
bisphosphate-dependent manner [43]. Cytoplasmic polyadeny- against transposable elements (TEs). TEs are major drivers in
lation by TENT5C stabilizes mRNA and enhances protein the evolution and diversity of genomes. New mutations
synthesis [40]. Nuclear non-canonical poly(A) polymerases caused by TEs may turn out to be beneficial in terms of
TENT4A/B were initially implicated in the induction of exo- gene regulation or RNA processing. Yet, organisms must
some-mediated RNA decay, but a recent report suggests that evolve defence mechanisms to restrict transposition. One
they can also stabilize mRNAs [44]. This is because of potent mechanism that organisms use to discriminate their
TENT4A/B’s sightly promiscuous nucleotide specificity, own DNA (self ) from foreign transposable DNA (non-self )
which leads to incorporation of guanine residues inhibiting is based on small RNA pathways. In addition to reviewing
deadenylation in the cytoplasm. the processes that restrict transposition in various organisms,
Zigáčková & Vaňáčová [45] describe in detail our current Ugolini and Halic point out that primal small RNAs must be
knowledge on the role of uridylation in RNA metabolism and degraded to avoid uncontrolled silencing. This degradation
physiology of the cell. These authors cite the key factors frequently involves the tailing of small RNAs and those
involved in the uridylation and degradation of RNAs, i.e. processes are detailed.
TUTases and 30 –50 exoribonucleases recognizing uridylated Altogether, these reviews and experimental reports illus-
RNAs. Zigáčková & Vaňáčová review all known types of trate the functional diversity of 50 and 30 modifications in
RNA substrates uridylated by TUTases. Those RNA controlling RNA stability and degradation. One important
conclusion that must be drawn from this compilation is that Data accessibility. This article has no additional data. 4
the list of modifications detailed in this theme issue is not Competing interests. We have no competing interests.

rstb.royalsocietypublishing.org
comprehensive. We are likely far from having an exhaustive
view of the types of modifications decorating the 50 and 30 Funding. D.G. acknowledges support from the Centre National de la
Recherche Scientifique (CNRS) and research grants from the
extremities of RNA, in addition to internal nucleotide Agence Nationale de Recherche (ANR) as part of the ‘Investments
modifications. Innovative technologies will keep fuelling for the Future’ program in the frame of the LABEX ANR-10-LABX-
unexpected discoveries in years to come, and we must be 0036_NETRNA and ANR-15-CE12-0008-01. A.D. acknowledges sup-
aware that we are just beginning to fully appreciate the real port from the ERC StG 309419 and NCN UMO-2013/10/M/NZ4/
impact of terminal RNA modifications in gene regulation. 00299 grant.

Phil. Trans. R. Soc. B 373: 20180160

Authors’ profile
Dominique Gagliardi is head of the ‘RNA degradation’ group at the Institut de Biologie Moléculaire
des Plantes (IBMP), a CNRS-driven research institute dedicated to plant biology and located at the
University of Strasbourg, France. His group focuses on the identification and characterization of
novel actors of RNA degradation pathways in plants, to determine their impact on genome
expression, on development and upon RNA virus infections. He and his colleagues are particularly
interested in understanding how 30 modifications by adenylation or uridylation control RNA’s fate.

Andrzej Dziembowski is a Professor of Molecular Biology at the Institute of Biochemistry and

Biophysics, Polish Academy of Sciences and at the Faculty of Biology, University of Warsaw. His
research focuses on the regulation of gene expression at the post-transcriptional level. He is particu-
larly interested in the mechanisms of RNA decay, and the role of enzymes modifying RNA 30 ends in
the determination of mRNA stability and translation potential. In his research, he uses various model
systems and advanced biochemical, transcriptomic and proteomic approaches.

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