Biology Reference
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all regulated by RNA-binding proteins (RBPs). Through direct interaction with
their target mRNAs, these RBPs control nuclear export, half-life, accessibility
by the translation machinery, and spliceosome targeting.
101,129-132
Recently,
several independent screens for DNA damage modulators identified RBPs as
important components of the DNA damage response. In a phospho-proteomic
mass spectrometry screen searching for direct targets of the DDR kinases
ATM, ATR, and DNA-PKcs in response to ionizing radiation, molecules
involved in mRNA regulation constituted a large subset of the identified kinase
substrates.
133
Moreover, when looking for spontaneous DNA damage in a
genome-wide RNAi screen, mRNA-binding proteins and molecules involved
in RNA processing were the most prominent group of identified factors.
134
Another genome-wide siRNA screen that was performed to search for novel
players in DNA damage signaling in response to ionizing radiation also iden-
tified proteins regulating RNA posttranslational modifications as one of the
most significant ''hits.''
135
Our understanding of how these mRNA regulatory factors are connected to
DNA damage signaling pathways is in its infancy. It is likely that the activity of
RBPs is directly regulated by kinases such as those implicated by the screen by
Matsuoka et al. for ATM and ATR.
133
Our lab recently identified RBPs as a major
target for the p38MAPK/MK2 pathway upon genotoxic stress involved in the
regulation of Gadd45
,
27
a cell cycle checkpoint protein that is induced after
a
genotoxic stress.
136,137
In addition to limited transcriptional control, Gadd45
a
levels are regulated posttranscriptionally.
138
The RBPs AUF1 and TIAR, which
negatively regulate Gadd45
mRNA and protein levels, rapidly dissociate from
its mRNA upon DNA damage, leading to increased mRNA stability and protein
accumulation.
139
The inhibitory function of TIAR is released through its direct
phosphorylation by p38 MAPK.
27
In addition, MK2 directly phosphorylates two
other regulators, hnRNPA0
140
and PARN, that were identified as novel Gadd45
a
a
mRNA-binding proteins.
27
The resulting accumulation of Gadd45
mRNA and
protein functions in a positive feed-forward loop that prolongs p38/MK2 activity
in later times after DNA damage, a function that appears to be especially
important in p53-defective cells
27
(reviewed in Ref.
141
).
A future challenge will be to identify additional critical mRNA targets in
the DNA damage response, the RBPs that control them, and the regulation of
these interactions between mRNA and mRNA regulatory proteins by DNA
damage response signaling pathways. Posttranscriptional regulatory mecha-
nisms are just emerging as a critical component in a cell's response to genotoxic
stress. Understanding this response in more detail, and with a special focus on
its oncogenic context, might open a new window of opportunity for the iden-
tification of synthetic lethal interactions with cancer-specific mutations, as well
as identifying a novel class of molecules for the design and development of
small-molecule inhibitors.
a
