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Andy Mehle
Translation of mRNA is a tightly regulated process, requiring
the ordered assembly of initiation factors and ribosomal
subunits. Initiation is a key regulatory step in controlled
gene expression. The primary mechanism of translation requires
recognition of a 5' 7-methyl guanosine cap and 3' poly A tail in
the mRNA for the coordinated assembly of a translation-competent
initiation complex. In contrast, certain viral and cellular
mRNAs utilize an internal ribosome entry site (IRES) for
translation independent of 5' cap recognition and when initiation
factors are limiting, circumventing traditional requirements for
translation initiation. IRES-mediated translation of cellular
transcripts may selectively regulate protein production during
critical cellular processes or stress responses when global
translation is significantly impaired. Genes suspected to be
regulated in this way are involved in fundamental cellular
processes including cell cycle regulation, angiogenesis,
development, and apoptosis.
Despite characterization of numerous proposed cellular IRES
RNAs, their mechanism(s) of translation initiation are not
yet known. Determining how IRES elements recruit ribosomes to
messenger RNAs, presumably by switching from a cap-dependent to
a cap-independent pathway, will be important for determining how
protein expression is regulated in response to environmental and
tissue-specific signals. These processes are intimately linked
to IRES structure, but the three-dimensional organization of
cellular IRESs is poorly understood. The goal of my project
in the Doudna lab is to provide a detailed biochemical and
structural understanding of a human cellular IRES.
A combination of biochemical, molecular, and cell biology
approaches will be used to initially characterize IRES
function and identify discrete elements amenable to structural
studies. Structural studies will identify the secondary
and three-dimensional structure of cellular IRES elements.
These findings will be integrated with data obtained from animal
studies regarding the role of IRES activity in development
and tumorigenesis. It is hoped that these results will yield
a detailed mechanistic understanding of IRES function and may
elucidate general mechanisms of cellular IRES activity.
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