Available online at www.sciencedirect.com
RNA dynamics: it is about time
Hashim M Al-Hashimi
1
and Nils G Walter
2
Many recently discovered RNA functions rely on highly
complex multistep conformational transitions that occur in
response to an array of cellular signals. These dynamics
accompany and guide, for example, RNA cotranscriptional
folding, ligand sensing and signaling, site-specific catalysis in
ribozymes, and the hierarchically ordered assembly of
ribonucleoproteins. RNA dynamics are encoded by both the
inherent properties of RNA structure, spanning many motional
modes with a large range of amplitudes and timescales, and
external trigger factors, ranging from proteins, nucleic acids,
metal ions, metabolites, and vitamins to temperature and even
directional RNA biosynthesis itself. Here, we review recent
advances in our understanding of RNA dynamics as highlighted
by biophysical tools.
Addresses
1
Department of Chemistry and Biophysics, University of Michigan, 930
North University Avenue, Ann Arbor, MI 48109-1055, United States
2
Department of Chemistry, Single Molecule Analysis Group, University
of Michigan, 930 North University Avenue, Ann Arbor, MI 48109-1055,
United States
Corresponding author: Al-Hashimi, Hashim M (hashimi@umich.edu) and
Walter, Nils G (nwalter@umich.edu)
Current Opinion in Structural Biology 2008, 18:321–329
This review comes from a themed issue on
Nucleic acids
Edited by Jennifer Doudna and Joseph Puglisi
0959-440X/$ – see front matter
# 2008 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.sbi.2008.04.004
Introduction
The ongoing discovery of a vast universe of noncoding
RNAs that perform widespread roles in living organisms
raises the fundamental question: How does a biopolymer
composed of only four chemically similar building blocks
realize such functional diversity? An emerging theme is
that much of RNA’s functional complexity is rooted not
only in the details of its intricate 3D structure but also
equally in its ability to adaptively acquire very distinct
conformations on its own or in response to specific cellular
signals including the recognition of proteins, nucleic
acids, metal ions, metabolites, vitamins, changes in
temperature, and even RNA biosynthesis itself. These
conformational transitions are spatially and temporally
tuned to achieve a variety of functions (Figure 1). For
example, they can guide folding pathways during RNA
cotranscriptional folding (Figure 1a); enable sensing and
signaling events that regulate gene expression in response
to changes in environmental conditions (Figure 1b); allow
ribozymes to dynamically meet the diverse structural
requirements associated with their multistep catalytic
cycles (Figure 1c); and enable complex ribonucleopro-
teins to assemble in a hierarchical and sequentially
ordered manner (Figure 1d).
RNA conformational transitions occur through complex,
often multilayer RNA dynamics that comprise a combi-
nation of thermally activated internal motions and re-
arrangements induced by external cofactors. Motions in
RNA range from rearrangements in secondary structure
and large-scale collective bending and twisting of helical
domains to more localized changes in base-pairing and
staking, sugar repuckering, and fluctuations along the
phosphodiester backbone, all of which occur over a range
of timescales (Figure 2). Over the past few years, comp-
lementary biophysical tools have provided distinct cross-
sectional views of RNA’s dazzling dynamical complexity
(Figure 2), leading to new insights that are reviewed here
with an emphasis on those derived from fluorescence and
NMR spectroscopy.
Self-induced transitions during
cotranscriptional folding
The RNA structural free energy landscape is highly
rugged so that different folding pathways can lead to
structurally distinct kinetically trapped intermediates. To
facilitate folding on such a landscape, many RNAs have
evolved to code for self-induced transitions involving
short-lived non-native structural motifs that dynamically
form during cotranscriptional folding (Figure 1a) [1].
Kinetic control over folding pathways becomes possible
in the cell because the rate of transcription (as fast as
$10
À3
s/nt) is relatively slow compared to folding of RNA
secondary structural elements (as fast as $10
À6
s)
(Figure 1). During 5
0
-to-3
0
transcription both native and
non-native secondary structure elements form efficiently,
beginning from the 5
0
-end, and survive long enough to
guide downstream folding along specific pathways
(Figure 1a). Conversely, upstream structural elements
are often still dynamic (short-lived) enough that compet-
ing downstream motifs or outside cofactors can efficiently
refold the RNA into an alternate (native) structure
(Figure 1a).
Studies are increasingly providing insights into the under-
lying code requirements and mechanisms for regulating
cotranscriptional RNA-folding via self-induced tran-
sitions. Xayaphoummine et al.[2] recently showed how
www.sciencedirect.com Current Opinion in Structural Biology 2008, 18:321–329