Dr. Yousif Shamoo
Structural Studies on Human recQL4
A group of autosomal recessive conditions including Rothmund-Thomson
and RAPADILINO Syndromes are caused by mutations to a human
DNA helicase, hRecQL4. hRecQL4 has a unique role in the
initiation of DNA replication that links mistakes early
in DNA replication to specific birth defects. We are determining
the structural basis for the developmental defects caused
by hRecQL4 using X-ray crystallography and electron microscopy
(EM). Together with information from genetic and biochemical
studies, the structure of hRecQL4 will drive development
of disease models that integrate aberrant DNA replication
to development.
Evolution of Antibiotic Resistance
The rise of antibiotic resistant pathogens is an important
clinical problem. We are using experimental evolution as
a predictive approach to understanding antibiotic resistance
as well as defining the general molecular mechanisms responsible
for adaptation. While experimental evolutionary biology
and genetics are powerful approaches to understanding the
fundamental mechanisms of evolution, our understanding of
the relationship of evolution to its physical origins remains
inadequate. We are studying the adaptation of microbial
populations to the ?-lactam and tetracycline classes of
antibiotics in order to elucidate the mutational pathways
that alter protein structure and function leading to increased
drug resistance. Once mutations are identified, the structure
and function of the altered proteins are studied using X-ray
crystallographic, specific activity and stability studies
to link the physicochemical characteristics of the protein
to the increased resistance/fitness of the organism.
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