response and Harmony Using a combined experimental and computational

response timing and mRNA half-lives. Furthermore,
they consistently found that highly unstable mRNAs
were enriched for AU-rich element. The authors con-
sidered also early and late downregulated genes, and
again found the same stability gradient associated
with response timing: early downregulated genes
were much less stable than late downregulated genes.
The biological conclusion is that the rst genes to
be activated or repressed by a cell response have a
short half-life and the last have a long half-life. This is
consistent with the discussion in the rst part of this
review, where it has been shown that speed of response
can be effectively achieved by a proper modulation
of transcript half-life. Elkon et al.22 elegantly proved
that the temporal order of gene activation/repression
and the sequential activation of transcription factors
could be ef ciently coordinated by a simple rela-
tionship between the transcription and degradation
machinery. Computational and experimental evidence
of the relationship between mRNA induction timing
and stability can also be found in malaria development
cycle,21 in budding yeast reproductive and metabolic
cycle18 and in mouse in ammatory processes.34 It is
worth noting that such posttranscriptional regulation
layer is likely to be intertwined with the transcrip-
tional activation/repression machinery layer, tightly
organized in space (e.g., cascade pattern) and time
(e.g., phosphorylation).43,44

Sleeping with the Enemy: Discord
and Harmony
Using a combined experimental and computational
approach, Shalem et al.45 have revealed two key
coordination strategies in yeast in response to envi-
ronmental stresses. They measured both mRNA con-
centration time pro les and decay rates genome-wide
in budding yeast after an oxidative stress and a DNA
damage stress. Then, they characterized the kinetics
of each gene by two key parameters: the decay rate
and the maximal fold change of the mRNA response.
By plotting these parameter pairs on a 2D space
(stability/folding diagram) they found two oppos-
ing simple rules for the coordination—on a global
scale—of decay rates and transcription peaks magni-
tude (Figure 5): (1) a ‘counteracting’ strategy, where
an increase (decrease) in decay rates is associated
with an increase (decrease) in mRNA magnitude, so
that repressed genes are stabilized and induced genes
are destabilized; (2) a ‘synergistic’ strategy, where an
increase (decrease) in decay rates is associated with
an decrease (increase) in mRNA magnitude, so that
activated genes are stabilized and repressed genes are
destabilized. The counteracting strategy is certainly

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somewhat surprising from a purely energetic point of
view. In fact, a high level of production associated to
a high level of destruction appears to be a waste of
energy, just like pressing hard both the gas and the
brake pedal of a car. Considering the previous discus-
sion it is clear that, by doing so, the cell response can
be very fast, e.g., it can display a very effective behav-
ior especially when facing life-threatening stresses.
However, such strategy is much more general than
one can imagine: experimental data of the malaria
plasmodium developmental cycle displays the same
strategy at the beginning of each cycle, as described
by Cacace et al.18 A variety of datasets recorded in
human murine cells covering many different aspects
of cellular physiology also displays the same feature.22
Computational analysis18 supports once again the
same hypothesis for early induced genes during the
reproductive and the metabolic cycle in budding
yeast. The large heterogeneity of the organisms and
biological processes displaying such property strongly
suggests that it might be a sort of ‘universal’ global
coordination strategy. This intriguing hypothesis is
still waiting for further experimental validation by the
measuring of both mRNA degradation and synthesis
rates46–49 in a variety of organisms and conditions.

CONCLUSION

Over the last decade, computational and experimen-
tal observations have clari ed the fundamental role
of mRNA decay in shaping cell response, in many
biological processes. Such growing evidence cannot
be underestimated, and therefore a large research
effort is needed to elucidate new mechanisms and
provide new insight into past experimental data. In
fact, modulation of mRNA turnover is already rec-
ognized as an important global regulator in cancer50
and as a potential drug target.51 In this brief review,
we mentioned the key role that properly orchestrated
and modulated decay rates may have in determining
the spatiotemporal ordering of events in biological
process such as cell cycle, growth, and development.

Another largely unexplored area of research is
‘how’ mRNA stability is coordinated with transcrip-
tional and posttranscriptional events. The picture
seems to become more and more complex every day,
as new experiments are reported in literature. An inter-
esting contribution to this issue is the work of Amorim
et al.52 on the meiotic gene expression program of
Schizosaccharomyces pombe. They showed a tight
cooperation between the transcriptional and post-
transcriptional control for the temporal regulation of
gene expression by means of the Mei4 transcription
factor which not only activates its targets but also