title: Optimal Down Regulation of mRNA Translation.
abstract: Down regulation of mRNA translation is an important problem in various bio-medical domains ranging from developing effective medicines for tumors and for viral diseases to developing attenuated virus strains that can be used for vaccination. Here, we study the problem of down regulation of mRNA translation using a mathematical model called the ribosome flow model (RFM). In the RFM, the mRNA molecule is modeled as a chain of n sites. The flow of ribosomes between consecutive sites is regulated by n + 1 transition rates. Given a set of feasible transition rates, that models the outcome of all possible mutations, we consider the problem of maximally down regulating protein production by altering the rates within this set of feasible rates. Under certain conditions on the feasible set, we show that an optimal solution can be determined efficiently. We also rigorously analyze two special cases of the down regulation optimization problem. Our results suggest that one must focus on the position along the mRNA molecule where the transition rate has the strongest effect on the protein production rate. However, this rate is not necessarily the slowest transition rate along the mRNA molecule. We discuss some of the biological implications of these results.
authors.affiliation: School of Electrical Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Zarai
authors.affiliation: School of Electrical Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Margaliot
authors.affiliation: Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.|Dept. of Biomedical Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Tamir
authors.initials: T
authors.lastname: Tuller
mesh_terms: D015536:Down-Regulation / Q000235:genetics*; D008954:Models, Biological; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: D012333:RNA, Messenger