The Cooperman laboratory in the Chemistry Department of the University of Pennsylvania is seeking to recruit a postdoctoral student with a strong interest in understanding the mechanism of action of nonsense suppressors (NonSups), a class of molecules that stimulate readthrough of mutant mRNAs containing a premature termination codon (PTC). PTC diseases, ranging from cancers to muscular dystrophy and cystic fibrosis, afflict millions of people worldwide. Despite the promise of NonSups, not a single NonSup has been approved by the FDA for treatment of PTC diseases, in part because of their toxic side effects. For some NonSups toxicity arises from their induction of generalized misreading of the genetic code. A critical barrier to further development of NonSups is the paucity of information regarding their mechanisms of stimulation of both readthrough and misreading and their target sites within the protein synthesis machinery of the cell. We developed a highly purified, eukaryotic cell-free protein synthesis system (Zhang et al., eLife, 2016, Jun 2;5. pii: e13429) which we have recently adapted to recapitulate NonSup-induced readthrough effects seen in live cell assays (Ng et al. ACS-Med Chem Lett 2018 DOI 10.1021/acsmedchemlett.8b00472). Our current work exploits the relative simplicity of this system to a) rapidly screen compound libraries for NonSup activity; b) elucidate the detailed mechanisms of NonSup stimulation of both readthrough and misreading of mRNA sequences ensemble and single molecule approaches, and c) identify the molecular targets of NonSups within the protein synthesis machinery. The results of these experiments in these areas should provide the basis for using rational design to find new NonSups with improved clinical effectiveness.
The successful applicant should be mechanistically oriented with expertise in biochemical and molecular biological approaches. Candidates with experience in reaction kinetics, including steady-state, pre-steady-state and single molecule measurements are preferred.
Qualifications include a Ph.D. (or equivalent training/degrees; within 1-3 years of graduation) in biochemistry, chemical biology, molecular biology or a related field and an interest in protein synthesis. Applicant must have a strong work ethic, communication & organization skills, and a willingness to think about and learn new methodologies as the projects evolves.
Interested applicants should send a cover letter and CV with contact information for three references to Barry Cooperman (firstname.lastname@example.org)
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