50 and 30 modifications controlling RNA
degradation: from safeguards to
rstb.royalsocietypublishing.org
Introduction
Cite this article: Gagliardi D, Dziembowski A.
2018 50 and 30 modifications controlling RNA
degradation: from safeguards to executioners.
Phil. Trans. R. Soc. B 373: 20180160.
http://dx.doi.org/10.1098/rstb.2018.0160
Accepted: 5 October 2018
One contribution of 11 to a theme issue ‘50
and 30 modifications controlling RNA
degradation’.
Subject Areas:
molecular biology
Keywords:
RNA modifications, RNA degradation, m7G cap,
poly(A) tail, polyadenylation, uridylation
Authors for correspondence:
Dominique Gagliardi
e-mail: dominique.gagliardi@ibmp-cnrs.
unistra.fr
Andrzej Dziembowski
e-mail: andrzejd@ibb.waw.pl
executioners
Dominique Gagliardi1 and Andrzej Dziembowski2,3
1
Institut de biologie moléculaire des plantes (IBMP), Centre national de la recherche scientifique (CNRS),
Université de Strasbourg, 12 rue Zimmer, 67000 Strasbourg, France
2
Laboratory of RNA Biology and Functional Genomics, Institute of Biochemistry and Biophysics,
Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
3
Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106
Warsaw, Poland
DG, 0000-0002-5871-7544
RNA degradation is a key process in the regulation of gene expression. In all
organisms, RNA degradation participates in controlling coding and non-
coding RNA levels in response to developmental and environmental cues.
RNA degradation is also crucial for the elimination of defective RNAs.
Those defective RNAs are mostly produced by ‘mistakes’ made by the RNA
processing machinery during the maturation of functional transcripts from
their precursors. The constant control of RNA quality prevents potential dele-
terious effects caused by the accumulation of aberrant non-coding transcripts
or by the translation of defective messenger RNAs (mRNAs). Prokaryotic
and eukaryotic organisms are also under the constant threat of attacks from
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
humans, and this together with the multiplicity of its roles illustrates the bio-
logical importance of RNA degradation. RNA degradation is mostly viewed
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
because the ultimate fate of any cellular RNA is to be eliminated. This special
issue focuses on modifications deposited at the 50 or the 30 extremities of RNA,
and how these modifications control RNA stability or degradation.
This article is part of the theme issue ‘50 and 30 modifications controlling
RNA degradation’.
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-
isms constitute the predominant part of pre-mRNA
molecules. Finally, 30 -end processing generates a mature 30
terminus, which is polyadenylated by canonical poly(A)
polymerases (ncPAPs) [6]. The only eukaryotic mRNAs
whose 30 end processing does not involve polyadenylation
are the replication-dependant histone mRNAs in mammals
[7]. Those particular mRNAs contain an RNA stem-loop
structure close to the 30 end of the mature RNA and are
processed by a specific mechanism. In addition to producing
pre-mRNA, independent transcription units produce precur-
sors of several other functional RNA classes (e.g. pre-rRNA,
pre-snRNA, pre-miRNA), as well as pervasive transcripts
such as long intergenic non-coding RNAs, many of which
play important regulatory roles [8]. Such RNAs are processed
by a variety of different mechanisms.
Although the decay of eukaryotic RNAs can be initiated by
endoribonucleolytic cleavages, it is mainly carried out by exo-
ribonucleases [9]. Therefore, 50 and 30 ends of RNA molecules
need to be protected. In the case of non-coding RNAs, this
protection is mostly achieved by shielding 50 and 30 extremities
within the ribonucleoparticle, which is formed by the non-
coding RNA and its associated proteins. A diversity of
processes can also contribute to the protection of extremities
of non-coding RNAs. For instance, 2-O’-methylation of the
last 30 nucleotide stabilizes all small RNAs in plants [10,11]
and piRNAs in animals [12]. In the case of mRNA, the 50
end is blocked by the m7G cap structure while the 30 end con-
tains a poly(A) tail. Nucleotides adjacent to the m7G cap can
be further methylated to either stabilize transcripts or increase
translation of certain mRNAs [13]. The m7G cap initially is
recognized by the nuclear cap binding complex, which facili-
tates mRNA export from the nucleus and is later replaced by
the essential translation initiation factor, eIF4E. Interestingly,
in addition to the classical m7G cap, a new type of cap, the
nicotinamide adenine dinucleotide (NADþ) cap was recently
identified in bacteria, yeast and humans [14,15]. In yeast and
humans, about 1–5% of mRNAs contain NADþ rather than
m7G cap. In contrast to m7G cap, the NADþ cap cannot
support translation in human cells and destabilizes mRNAs
through the deNADding activity of the DXO proteins [16].
The discovery of alternative caps and the elucidation of their
function are certainly exciting areas of research.
At the other end of the mRNA, the poly(A) tail is bound by
poly(A) binding proteins (PABPs), which facilitate mRNA
export from the nucleus and enhance protein synthesis through
interactions with translation initiation factors [17]. Poly(A) also
stabilizes mRNA molecules by preventing exoribonucleolytic
decay. Consequently, the deadenylation rate largely determines
mRNA half-life. Shortening a poly(A) tail in the cytoplasm to
fewer than 15–20 nt destabilizes its interaction with the last
PABP [18,19]. Once this last PABP is released, the mRNA
becomes translationally inactive and susceptible to degradation,
either through the decapping and 50 to 30 decay or by 30 to 50
decay pathway. However, it is now appreciated that poly(A)
tail dynamics is more complex than previously suspected.
Deadenylated mRNAs can be uridylated [20–22] or stored in
a dormant state to be later re-adenylated to activate protein
synthesis [23–26]. Such reactions are mediated by terminal
uridylyltransferases (TUTases) and non-canonical poly(A)
polymerases. Interestingly, the non-canonical addition of non-
templated nucleotides is important for the physiology of not
only mRNAs but also other RNA classes such as pre-miRNAs,
mature miRNAs or nuclear non-coding RNAs. Such modifi- 2
cations can stabilize RNA molecules or induce their decay.
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Of note, the destabilization of RNA by nucleotide tailing is a
conserved process across organisms and it was identified in
Escherichia coli [27]. Although in bacteria, bulk RNA decay is
initiated by endonucleolytic events, the ends of RNA molecules
also play an important role in controlling RNA fate. Secondary
structures may impede the progression of 30 to 50 exoribonu-
cleases and polyadenylation accelerates the degradation of
RNA decay intermediates facilitating the action of 30 to 50 exo-
ribonucleases. Moreover, the triphosphate moiety present at the
50 end of the primary transcripts restricts endonucleolytic clea-
Phil. Trans. R. Soc. B 373: 20180160
vage by the RNase E and its conversion to monophosphate
accelerates the decay rates of many, but not all, transcripts [28].
Because of the impact of the ends of RNA molecules on
their stability and biological functions, all RNA modifications
must be tightly controlled, and complex regulatory networks
of protein–protein and protein–RNA interactions are involved
in capping/decapping, polyadenylation/deadenylation and
uridylation. This field of research is currently expanding, and
several key discoveries were made in recent years. This
theme issue of Philosophical Transactions B entitled ‘50 and
30 modifications controlling RNA degradation’ gathers articles
explaining how 50 and 30 RNA modifications control the decay
of coding and non-coding RNAs. The first three articles focus
on the cap structure, followed by seven articles about various
aspects of RNA tailing by non-canonical poly(A) polymerases
and TUTases.
Charenton et al. [29] describe how the removal of the 50
end cap structure is regulated, focusing on the mechanistic
aspect. Although the elimination of the mRNA m7GpppN
cap is a simple chemical reaction catalysed by the Nudix
family hydrolase Dcp2, this enzyme has intrinsically very
weak activity [30]. Thus, it requires several accessory factors
that enhance its activity. In recent years, there has been
considerable progress in our understanding of how all these
proteins such as Dcp1, Lsm1–7 complexes, Pat1, Edc1–
Edc2 and/or Edc3 cooperate with Dcp2 to ensure that
removal of the mRNA cap structure is tightly controlled.
Toczydlowska-Socha et al. [31] describe RNA helicase
DDX15 as a novel regulator of cap methylation. In contrast
to yeast, the vertebrate m7GpppN cap can be post-transcrip-
tionally modified at the first nucleotide by RNA cap1
methyltransferase (CMTr1) [32,33]. Such modification is
believed to play a role in antiviral defence [34]. Very little is
known about the regulation of CMTr1-mediated cap modifi-
cation. The authors identified RNA helicase DHX15 as a
CMTr1 interactor. They further show that CMTr1 activity is
hindered towards RNA substrates with highly structured 50 -
termini and DHX15 facilitates methylation of such RNA
species. The physiological role of this effect remains to be
established, but this article describes the first example of
regulated 2’-O-ribose methylation of the mRNA cap structure.
Because of the importance of the cap structure for mRNA
stability and protein synthesis, there is a clear need for the
development of novel tools for the analysis of mRNA cap
metabolism [35]. Bednarek et al. [36] invented several novel
biotin-labelled cap analogues modified within the tripho-
sphate bridge to increase their stability in cellular
conditions. They are efficiently incorporated into RNA
in vitro and can be applied to a variety of different exper-
iments including protein affinity purification, pull-down
assays, in vivo visualization, cellular delivery, etc.
 The first contribution of the seven articles that focus on
the tailing of RNA 30 ends is by Hajnsdorf and Kaberdin
[37], who describe how oligoadenylation facilitates RNA
decay in bacteria. Hajnsdorf and Kaberdin present the
machinery responsible for the oligoadenylation of bacterial
RNAs and their degradation. They focus mostly on the
knowledge obtained in E. coli, because the seminal discov-
eries in this field were made using this model organism.
Yet, work performed on evolutionarily distant bacteria is
also mentioned. Hajnsdorf and Kaberdin summarize the
known RNA targets of oligoadenylation in E. coli to define
the impact of oligoadenylation on gene expression.
By reading the following review by Tudek et al. [38], an
interesting comparison can be made between the complexity
of roles played by oligo/polyadenylation in bacteria versus
eukaryotes. Tudek et al. focus on the intricate role of
poly(A) tails in controlling RNA fate in the nucleus of bud-
ding yeast and human cells. Although polyadenylation of
eukaryotic mRNAs is known to promote stability, export
from the nucleus and translation, oligoadenylation also oper-
ates as an RNA destabilizing tag in eukaryotic nuclei. This
RNA destabilizing role of oligoadenylation is therefore con-
served across evolution, from bacteria to man, and it
actually represents the primordial role of oligoadenylation.
Tudek et al. provide a detailed view of the different mechan-
isms and factors leading to the polyadenylation of eukaryotic
RNAs. One could think that the distinction between the pro-
cesses leading to destabilization or stabilization by
polyadenylation is straightforward. On the contrary, Tudek
et al. demonstrate that this boundary is becoming increas-
ingly uncertain, with both pathways sharing common factors.
The next review article is by Warkocki et al. [39], who
summarizes our current knowledge about all mammalian
ncPAPs and TUTases. Previously, 7 ncPAPs and TUTases
have been annotated in the human genome. Recently, a new
TENT5 (FAM46) family of four members has been identified
[40,41]. Thus, the human genome encodes at least 11 ncPAPs
and TUTases. Our knowledge about these enzymes is very frag-
mentary and in many cases there are conflicting reports about
their substrate specificity. Nonetheless, it is an exciting field of
investigation and several recent reports indicate that they have
important, although diverse, physiological roles. For instance,
uridylation by TUT7/TUT4 in the cytoplasm induces decay of
various RNA species and protects cells against viruses and
LINE-1 retrotransposons. Nuclear TUTase (TUT1) is involved
in U6 snRNA 30 end formation [42] and was also suggested to
polyadenylate a subset of mRNAs in a phosphatidylinositol
bisphosphate-dependent manner [43]. Cytoplasmic polyadeny-
lation by TENT5C stabilizes mRNA and enhances protein
synthesis [40]. Nuclear non-canonical poly(A) polymerases
TENT4A/B were initially implicated in the induction of exo-
some-mediated RNA decay, but a recent report suggests that
they can also stabilize mRNAs [44]. This is because of
TENT4A/B’s sightly promiscuous nucleotide specificity,
which leads to incorporation of guanine residues inhibiting
deadenylation in the cytoplasm.
Zigáčková & Vaňáčová [45] describe in detail our current
knowledge on the role of uridylation in RNA metabolism and
physiology of the cell. These authors cite the key factors
involved in the uridylation and degradation of RNAs, i.e.
TUTases and 30 –50 exoribonucleases recognizing uridylated
RNAs. Zigáčková & Vaňáčová review all known types of
RNA substrates uridylated by TUTases. Those RNA
substrates include nuclear and cytosolic RNAs, coding and 3
non-coding, and also viral RNAs. The different roles of
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RNA uridylation are then explained. This description is not
restricted to various degradative mechanisms but also
includes the role of uridylation in promoting maturation,
and possibly controlling localization or translation.
De Almeida, Scheer et al. [46] focus on RNA uridylation in
plants. The uridylation of various RNA substrates has been
investigated in plants, from small RNAs and other non-
coding RNAs, to mRNAs. Most of the knowledge on plant
RNA uridylation was obtained using the flowering plant Arabi-
dopsis thaliana, but seminal work was also done in the green
Phil. Trans. R. Soc. B 373: 20180160
algae Chlamydomonas reinhardtii. Both forward and reverse gen-
etic strategies led to the identification of two distinctive
TUTases in these model plant species: MUT68/HESO1 and
URT1. De Almeida, Scheer et al. report a detailed evolutionary
history of both TUTases in Archaeplastida (i.e. all plants).
HESO1 and URT1 homologues each form a monophyletic
group, and the presence of both TUTases has been maintained
in almost all species of the green lineage, indicating specific and
critical functions. De Almeida, Scheer et al. then recapitulate the
diverse molecular functions of both TUTases during RNA
degradation processes in plants and conclude with key points
of future research.
The article by Meaux and co-authors [47] combines a
review of our current knowledge on how uridylation induces
decay of replication-dependent histone mRNAs in mammals,
with new information on two molecular players involved in
this process: the serine/threonine protein kinase Smg1 and
the RNA helicase Upf1. Replication-dependent histone
mRNAs in mammals are the only mRNAs that are not poly-
adenylated. Instead of a poly(A) tail, they end with a short
stem-loop structure. The levels of those mRNAs are tightly
regulated, with a massive degradation at the end of the
S-phase or in response to inhibition of DNA synthesis. This
degradation involves uridylation and, besides TUTases,
key factors like the stem-loop binding protein (SLBP) or the
exoribonuclease, 30 hExo (ERI1). Meaux et al. bring new infor-
mation on the involvement of Upf1 domains in this process
and report that the kinase Smg1 is required for histone
mRNA degradation when DNA replication is inhibited. In
addition, they show by using a strategy based on high-
throughput sequencing, that the pathway of rapid histone
mRNA degradation is identical at the end of S-phase or
when DNA replication is inhibited in S-phase.
The final article in this issue by Ugolini and Halic [48]
gives an overview of the mechanisms of RNA-based defence
against transposable elements (TEs). TEs are major drivers in
the evolution and diversity of genomes. New mutations
caused by TEs may turn out to be beneficial in terms of
gene regulation or RNA processing. Yet, organisms must
evolve defence mechanisms to restrict transposition. One
potent mechanism that organisms use to discriminate their
own DNA (self ) from foreign transposable DNA (non-self )
is based on small RNA pathways. In addition to reviewing
the processes that restrict transposition in various organisms,
Ugolini and Halic point out that primal small RNAs must be
degraded to avoid uncontrolled silencing. This degradation
frequently involves the tailing of small RNAs and those
processes are detailed.
Altogether, these reviews and experimental reports illus-
trate the functional diversity of 50 and 30 modifications in
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.

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