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Laboratory of Biochemistry and Genetics

Using genetics, molecular biology, and physical chemistry to study translation, diseases of protein aggregation, and basic problems in development, growth, polyamines, and molecular crowding in model organisms.
About the Lab

Lab Sections & Chiefs

Genetics of Early Development

Andy Golden, Ph.D., Section Chief

We are currently modeling a number of rare human genetic diseases in C. elegans. Our goal is to identify the regulators and interactors of conserved genes in C. elegans, that when mutated, can cause human disease. Understanding the genes that interact with a disease gene will shed light on the genetic pathway in which the disease gene acts. By activating or inhibiting the activity of interacting genes, it may be possible to alleviate symptoms of the disease. Thus, genetic screens to identify interacting genes may lead to novel therapeutic targets.

Genetics of Organelle Biogenesis Section

Kevin F. O'Connell, Ph.D., Section Chief

The Genetics of Organelle Biogenesis Section studies the biogenesis and function of centrioles, non-membrane bound organelles that play key roles in cell division, motility, and signaling. A growing number of diseases including cancer, autosomal recessive primary microcephaly, and polycystic kidney disease, have been linked to defects in centriole number and/or function. Thus, our work should lead to a better understanding of the normal regulatory mechanisms governing centrioles and how these processes go awry in disease.

Genetics of Simple Eukaryotes Section

Reed B. Wickner, M.D., NIH Distinguished Investigator, Section Chief

The Genetics of Simple Eukaryote Section uses S. cerevisiae to study infectious diseases, particularly prions (infectious proteins). By examining the structure of the amyloids underlying most yeast prions, and the genetics of prion propagation and generation we have obtained an understanding of how proteins can be the basis of genetic information propagation, discovered several means of curing prions, and obtained information that will likely be useful in studies of human amyloidoses.

Pharmacology Section

Herbert Tabor, M.D., Section Chief

The Pharmacology Section studies the polyamines—putrescine, spermidine, and spermin—which are major polybasic compounds in all living cells. These amines are important for many systems related to growth and differentiation. To investigate how these polyamines are synthesized, how their biosynthesis and degradation are regulated, their physiologic functions, and how they act in vivo, we have made null mutants in each of the biosynthetic steps in both Escherichia coli and in S. cerevisiae. We find that the polyamines are required for growth of the organisms, sporulation, maintenance of the killer dsRNA virus, protection against oxidative damage, protection against elevated temperatures, fidelity of protein biosynthesis, and maintenance of mitochondria. We constructed clones that overproduce these enzymes and studied the sequence, structure, and regulation of these enzymes (e.g., ornithine decarboxylase, spermidine synthase, spermine synthase, and S-adenosylmethionine decarboxylase). Present studies are concerned with how polyamines stimulate the level of the RpoS subunit of E.coli RNA polymerase, and the action of polyamines in correcting the defect in the wobble position of aminoacyltRNA due to an mnmE chromosomal deletion.

Physical Biochemistry Section

Allen P. Minton, Ph.D., Section Chief

The Section on Physical Biochemistry is engaged in quantitative studies of effect of high concentrations of nominally inert small molecule and macromolecular cosolutes on the thermodynamic and hydrodynamic behavior of selected proteins and nucleic acids. The identification and characterization of such effects is essential for an understanding and quantitative prediction of the functional behavior of proteins and nucleic acids within complex physiological media. These studies are carried out both theoretically and experimentally, often using concepts and experimental tools developed in our laboratory.

Protein Chaperones and Amyloid Section

Daniel C. Masison, Ph.D., Section Chief

The Protein Chaperones & Amyloid Section identifies and charcterizes cellular factors that influence propagation of the S. cerevisiae [PSI+] prion. [PSI+] is thought to be an amyloid form of Sup35, a protein involved in termination of protein synthesis. About two dozen human disorders, which include Type 2 diabetes and Alzheimer's disease, are associated with accumulation of amyloid forms of proteins. In addition to simply growing, transmissible [PSI+] particles, or prion "seeds", must replicate to be maintained in a growing yeast population. Research in this section provides a better understanding of how protein chaperones (Hsp70, Hsp40, and Hsp104) and TPR co-chaperones function in amyloid propagation. The normal function of this chaperone machine appears to promote amyloid propagation by breaking fibers into more numerous pieces, each of which can continue to propagate the amyloid structure. Section researchers have identified several mutations in these chaperones that variously affect the [PSI+] seeding process—findings that will improve understanding of the underlying molecular mechanisms.

Section on mRNA Regulation and Translation

Nicholas R. Guydosh, Ph.D., Stadtman Tenure-Track Investigator, Acting Section Chief

Research in this section is aimed at understanding the mechanism of mRNA translation by the ribosome and the functional outcomes of translational regulation. Since translation is a key step in the expression of genes, this work will inform development of therapies for numerous diseases, including cancer and infectious disease. Current investigations are focused on the final stages of translation when the newly-synthesized protein is released by the ribosome and the ribosomal subunits are recycled for reuse.