Biology Reference
In-Depth Information
relationships between these 'step' clusters in the hierarchy
also reflect broader functional similarity (Figure 8.3). For
example, the precursor and cytosolic ribosomal large
subunit (LSU) clusters are closely related in the hierarchy.
A hallmark of stress is a rapid reprogramming of
translation; translation is first sharply downregulated, while
a few select transcripts are translationally upregulated,
facilitating adaptation and promoting survival. The trans-
lation of mRNAs is a key regulatory point that is often
controlled through the rate-limiting translational initiation
step, which requires a complex interplay between trans-
lation initiation factors
[84,85]
. Ribosome profiling has
also revealed that translation can be regulated through
many distinct mechanisms, including, for example, specific
translational uORF upregulation
[86]
, stress granules that
inhibit translation of specific transcripts
[87]
, blocking of
ribosomal subunit export at the nuclear pore complex
[88,89]
, mRNA decay of specific transcripts, regulation
mediated by the TOR pathway
[21,61,64,90]
, control of
ribosome biogenesis
[89]
, alternate splicing
[87]
, and co-
regulation of transcription and translation
[91]
. The relative
contributions of these diverse processes are often stress
specific. In light of the many ways in which translational
regulation can occur; the NPC, SG, TL, RNAP and RB
module, our MDR network may not reflect a requirement.
For example, ribosomal biogenesis may not be required for
resistance to chemical stress per se, but its presence in the
MDR network is instead is indicative that the translational
reprogramming required during stress is mediated through
these processes.
In light of the many translational regulatory mecha-
nisms cited above, the novel modules in our MDR network
may be connected by the following series of events that
together define the cellular response to chemical stress: (1)
global translational arrest, mediated by mechanisms that
require genes represented in any or a combination of the
NPC, RB, RNAP and TL modules; (2) mRNAs freed by
aborted translation are sorted for different fates, either
selective degradation (P-bodies) or storage/translational
inhibition/trapping of translation initiation factors and 40S
subunits in stress granules, requiring genes represented by
the SG module; and (3) selected key genes or mRNAs are
translationally upregulated (i.e., those not trapped by stress
granules) by mechanisms that often include uORF and
alternative splicing-enhanced translation
[87]
, and may
also involve many of the same mechanisms as those
required for decreased translation. Finally, the select
upregulated proteins act to adapt to stress and/or restore
cellular homeostasis.
The literature cited above supports this general view of
the cellular response to stress. Collectively, a new perspec-
tive of the cell has emerged, one where many genes
are regulated by post-transcriptional and translational regu-
latory mechanisms
[92
mechanisms. During stress, translation is the dominant
regulatory mechanism
[95]
allowing for a rapid response,
that can later be supplemented by increased or decreased
transcription. This translational view of the cell is also
supported by mammalian studies
[96]
. Moreover, many of
the unique regulatory mechanisms, processes and even
cellular components (e.g., P-bodies and stress granules)are
activated only during conditions of stress, and the precise
response (e.g., acting through one or a few genes) is specific
to the particular stress condition. Several of these newly
discovered post-transcriptionally regulated mechanisms
have been recently linked to the progression of cancer
[72,97]
, and may indicate potential mechanisms of cancer
progression that enable cells to escape the many fail-safe
mechanisms of this system
[72]
. This new research avenue
has also been suggested as a rich source to mine for novel
drug targets
[98]
. Albeit preliminary, the MDR network that
emerged from our chemogenomic dataset pulls together
many of the individual studies cited into a coherent frame-
work that defines several novel mechanisms of resistance to
stress, and thus the existence of this network represents an
important biological discovery.
Further analyses combined with hypothesis-driven
experiments are required to fully characterize and study the
behavior of this network. Significantly, our first study of
~400 diverse environment and small molecule perturba-
tions did not uncover the existence of this chemical stress
response network, suggesting that the collection of a data-
set an order of magnitude larger was essential to uncover
this new biology, and supports a view that the dataset
carries biologically rich information that can be explored at
multiple levels of resolution. Overall, our MDR network
exhibits many characteristics that are reminiscent of
quiescence, rapamycin-induced inhibition of TOR and
nitrogen starvation. Translational regulatory mechanisms
may serve as a central control center; insulating the cell
from chemical or other stress, activating stress-specific
response mechanisms at precisely defined point in the
network as needed, temporarily turning off translation,
reducing growth, actively accumulating mRNAs in storage
granules in the cytoplasm, and preparing the cell for rapidly
restoration all systems when a favorable environment
presents itself. In summary, although much analysis and
further study lie ahead, the MDR network captures the first
comprehensive genome-wide view of the cellular response
to chemical stress, defining potentially novel resistance
mechanisms that may be shared by other 'cellular states'
and/or stress mechanisms.
Chemical Structures Associated with MDR
Biological Processes
In addition to revealing the properties of the cellular
response to chemical stress, we can refine our understanding
94]
and fewer by transcriptional
e
