Dr. Dale Cameron
Assistant Professor
Office: Thomas 002, Ph: 610-409-3222
Email: dcameron1@ursinus.edu

Education and training:

B.Sc.(Hons), University of New South Wales, Sydney, Australia
Ph.D., University of New South Wales, Sydney, Australia
Visiting Research Scholar, Brown University
Postdoctoral Fellow, University of California, San Francisco

BIO102 Cell Biology and Genetics of Health and Disease (Lecture and Lab)
BIO201L Genetics and Biology of the Cell (Lab)
BIO350.A Protein Biogenesis

In my lab we study the role of protein misfolding and aggregation in both normal biology and disease states using the budding yeast Saccharomyces cerevisiae (baker’s yeast). Proteins carry out many different tasks in cells, but in order to be functional each protein must first fold into the correct three dimensional structure (or conformation). Most proteins are able to fold into multiple conformations, and ensuring each protein adopts the correct structure is an important challenge for cells. Misfolded proteins cannot carry out their normal functions and may sometimes even take on new, potentially toxic functions. In addition, many misfolded proteins coalesce to form large insoluble aggregates. To help minimize the potentially deadly consequences of protein misfolding and aggregation, cells have evolved a complex system of cellular factors to refold or degrade misshapen proteins. However, in some circumstances these quality control systems are inadequate; indeed, protein misfolding plays a key role in the pathogenesis of many diseases, including Alzheimer’s, Huntington’s and Parkinson’s diseases, as well as the various mammalian prion diseases. Prions (“pree-ons”) are composed of misfolded proteins that tend to form aggregates; however, prions are a very unique class of misfolded proteins because their misshapen aggregation-prone conformation can replicate and propagate infectiously (much like viruses do). Prions are the cause of diseases like “mad cow” disease, scrapie in sheep, chronic wasting disease in deer and elk, and Creutzfeldt-Jakob disease in humans. Underlying all of these diseases is the conversion of a normal protein molecule into the misfolded prion conformation, which then acts as a template to convert yet more molecules of the correctly folded protein into the prion form. Thus, once initiated, prion replication proceeds in a self-propagating, auto-catalytic manner (figure 1).

Although prion diseases are rare, a prion-like mechanism of propagating protein aggregates is likely ubiquitous. For example, several traits in fungi result from a prion-like mechanism of inheritance. However, unlike the mammalian prions, these fungal prions are not pathogenic and may sometimes even be beneficial to the cell. The discovery of multiple different prions in yeast has prompted the suggestion that they may serve some biological function. For example, the yeast prion [PSI+] results from the aggregation of a protein called Sup35, which normally functions in the termination of protein synthesis at stop codons. The loss of Sup35 function that occurs upon its conversion to the prion form leads to read-through of stop codons and the generation of many new types of proteins in the cell; consequently, the [PSI+] prion has a profound influence on protein synthesis, which may modulate cellular fitness in a given environment. In the lab, we have engineered the yeast so that we can easily determine whether a population of cells has the [PSI+] prion simply by observing the colony color: red cells are prion free (termed [psi-]), whereas white-pink cells contain the prion ([PSI+]; Figure 2).

All known yeast prion proteins contain segments that are rich in the amino acids glutamine and asparagine, which have a strong tendency to aggregate. Despite the potential toxicity of protein aggregation, eukaryotic cells contain many proteins carrying highly aggregation-prone regions. The sheer abundance of these proteins and the diversity of their functions suggest there may be a broader role for protein aggregation in normal cellular biology. To date, the potential for modulating protein function via regulated aggregation remains largely uncharacterized. Moreover, cellular factors that modulate or circumvent the potential toxicity of these aggregates are poorly defined. In other words, why do some protein aggregates appear to be toxic whereas others are benign and perhaps even functionally important?

In my lab we use a combination of genetics, cell biology and biochemistry to address several broad questions related to protein misfolding and aggregation. What is the role of protein aggregation in normal biology and how does this phenomenon affect cellular physiology? Why do prions exist, and can we identify novel prions? Finally, how do cells protect themselves from the potentially toxic consequences of expressing aggregation-prone proteins?

Select publications:

Breslow DK*, Cameron DM*, Collins SR, Schuldiner M, Stewart-Ornstein J, Newman HW, Braun S, Madhani HD, Krogan NJ and Weissman JS (2008). A comprehensive strategy enabling high-resolution functional analysis of the yeast genome. Nature Methods 5, 711-718.
*co-first authors
Featured as a Research Highlight in Nature Reviews Genetics 9, 571 (2008)

Cameron DM, Gregory ST, Thompson J, Suh M-J, Limbach PA and Dahlberg AE (2004). Thermus thermophilus L11 methyltransferase, PrmA, is dispensable for growth and preferentially modifies free ribosomal protein L11 prior to ribosome assembly. Journal of Bacterioogy 186, 5819-5825.

Cameron DM, Thompson J, Gregory ST, March PE and Dahlberg AE (2004). Thiostrepton-resistant mutants of Thermus thermophilus. Nucleic Acids Research 32, 3220-3227.

Cameron DM, Thompson J, March PE and Dahlberg AE. (2002). Initiation factor IF2, thiostrepton and micrococcin prevent the binding of elongation factor G to the Escherichia coli ribosome. Journal of Molecular Biology 319, 27-35.

Koosha H, Cameron D, Andrews K, Dahlberg AE and March PE. (2000). Alterations in the peptidyltransferase and decoding domains of ribosomal RNA suppress mutations in the elongation factor G gene. RNA 6, 1166-1173.