DELA CRUZ, Marie Giecel V.

2008 67965 BS Biochemistry BC121

Epigenetics in the Extreme: Prions and the Inheritance of Environmentally Acquired Traits (A critique)

Randal Halfman and Susan Lindquist attempted to illustrate the importance of prions in the inheritance of traits in their October 2010 SCIENCE article. At the time, there are still many mysterious things surrounding the concept of prions and their relation to molecular evolution but they are already known to affect and induce changes not only within their domains but also in other domains surrounding them. In the first part of the article, Halfman and Lindquist provided a brief introduction on the role of prions in epigenetics and how it operates inside the system. They also introduced the modern definition of epigenetics, in context, of how they are going to use the term for their article, using Rando and Verstrpens (2007) definition. The authors, Halfman and Lindquist, mentioned that prions perpetuate not by changing the way that genetic information is transcribed or translated but rather by co-opting the final step in the decoding of genetic information. The final step in the decoding of genetic information refers to the process of protein folding or the conformation of proteins into their functional structure that will allow normal bodily processes to occur normally. The authors provided clear examples on the way prions serve as elements of inheritance, illustrating first the way Saccharomyces cerevisiae created protein domains that alter its biochemical activity. They also showed the process by which prions replicate themselves through a series of conformational conversion and polymer propagation. It was also stated that fluctuations in the dissemination of cells with prion conformation can result to daughter cells with non-prion conformation, depending on many factors surrounding the replication, since prion states of proteins are not irreversible. According to Halfman and Lindquist, there already many known proteins that form prion states in S. cerevisiae alone and more are being experimentally verified currently. They gave the example of the protein, Sup35, one of the best understood prion proteins to date. It functions as a translation termination factor by switching to prion conformation. This ability to switch to prion conformation in S. cerevisiae has been conserved by the organism for many years now and the process results to a phenotypic change, including resistance to various toxins and antibiotics. Knowledge of this can be used in developing drugs that will combat the disease-causing strains of S. cerevisiae in mammals. In the second part of the article, the authors showed how prions could diversify protein functions in organisms. It was mentioned that prion conformation brings about phenotypic changes, and these

changes resulted from the alteration of protein function when the change in structure occurred. It is common knowledge that a specific protein folding equates to a specific interaction to its environment and

slight changes could result to loss of function or, in prion state, gain of function. Prion proteins often form new interactions with other proteins not interacted with normal nonprion proteins. The authors provided some examples of this gain of function from switching to prion state such as the Rnq1 protein of S. cerevisiae which stimulates other proteins to switch to prion state and the Sfp1 protein which normally acts as translation regulator and increases cell growth when in prion state because of the resulting ability to resist translational inhibitors. They also mentioned the ability of prions to switch between normal conformation and prion conformation in the third part of the article. This is an interesting theory considering that, according to the authors, this switch from one conformation to another is induced by the amount of stress present in the environment. Abrupt changes in the environment result to changes in protein folding and could either promote or block prion formation. This is where the extreme part of prions role in epigenetics come in. Stress levels can drastically increase or decrease the amount of prions present in a cell. Prion formation or disassembly allows the organism to adapt to sudden changes in the environment. If the change is proven to be beneficial, the organism will keep producing the phenotype in order to survive its new environment. Exposure to changes in environment that result to formation of new phenotypes from prion states of proteins allow appearance of complex traits. In the fourth part of the article, the concept of phenotypic capacitance was introduced. It is the ability of biological systems to allow accumulation of genetic variation in silent forms. These variations create new phenotypes that will be released when needed. Prions allow cells to switch from one state to another, as mentioned previously, and this is a clear example of its ability to be natural inducers of genetic variation. Prions can be transmitted from mother to daughter cell during replication, along with nonprion proteins and this creates diversity in the population of the organisms by being ingrained in the genetic code, eventually, after several generations of transmission. To date, there are many advances in prion and prion formation studies that it will provide long term effects in relating this branch of study to that of other concepts in epigenetics. Authors are hoping for further advancements in the understanding of prions and their functions in cells and they are in promoting the idea that prions are not simply disease-carrying mutations in the cell but also great contributors in the flow of genetic information. Prions are able to alter the function of cells on the larger scale and proteomic studies are able to provide more insight on the phenotypic effects that result from these interactions of prions to nonprion proteins or other prion proteins as well.