ETS proteins are a group of evolutionarily related, DNA-binding
transcriptional factors. These proteins direct gene expression in
diverse normal and disease states by binding to specific promoters and
enhancers and facilitating assembly of other components of the
transcriptional machinery. The highly conserved DNA-binding ETS domain
defines the family and is responsible for specific recognition of a
common sequence motif, 5'-GGA(A/T)-3'. Attaining specificity for
biological regulation in such a family is thus a conundrum. We present
the current knowledge of routes to functional diversity and DNA binding
specificity, including divergent properties of the conserved ETS and PNT
domains, the involvement of flanking structured and unstructured
regions appended to these dynamic domains, posttranslational
modifications, and protein partnerships with other DNA-binding proteins
and coregulators. The review emphasizes recent advances from biochemical
and biophysical approaches, as well as insights from genomic studies
that detect ETS-factor occupancy in living cells.
Dynamics
are increasingly implicated as a powerful regulatory mechanism in
protein function. Studying how intra- and intermolecular interactions
establish the amplitude and timescale of these dynamics—and, thus
potentially, the DNA-binding properties of transcription factors—is a
new avenue for understanding the regulation of gene expression.
Biophysical studies of increasing sophistication will help define the
physicochemical bases for ETS autoinhibition and dissect the role of
dynamics in protein and target DNA recognition by the PNT and ETS
domains, respectively.
A high level of
redundant genomic occupancy in the ETS family was detected in promoter
proximal regions. Further work will determine whether ETS proteins play a
redundant mechanistic role in transcription regulation at these targets
and whether these sites have functions distinct from more distal
enhancer elements.
As genome-wide binding
data become available for more ETS proteins, as well as other
transcription factors, comparisons will allow classification of
redundant, specific, and partially specific binding sites. This
categorization will improve the robustness of the new data sets to
investigate mechanisms that enable specificity within the ETS family,
including composite elements for cooperative binding partnerships and
other routes to synergistic transcriptional regulation. Redundancy
within subfamilies versus the entire family needs to be clarified.
The
ETS genes that are involved in chromosomal abnormalities in solid
tumors are limited largely to those in ERG and PEA3 subfamilies. It is
not known to what degree the oncogenic functions of these genes overlap.
Determining the specific roles of these two subfamilies, compared with
the rest of the ETS family, will be important to understanding the
mechanisms of ETS-mediated oncogenesis.
The
development of therapeutic strategies, including small-molecule
modulators of protein interactions, to regulate ETS proteins could have
high clinical impact. Currently available and new structural and
biochemical information about ETS proteins will be valuable in achieving
this challenging research goal.
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