Persistent Link:
http://hdl.handle.net/10150/320007
Title:
Stochastic Models of –1 Programmed Ribosomal Frameshifting
Author:
Bailey, Brenae L.
Issue Date:
2014
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Many viruses can produce multiple proteins from a single mRNA sequence by encoding the proteins in overlapping genes. One mechanism that causes the ribosomes of infected cells to decode both genes is –1 programmed ribosomal frameshifting. In this process, structural elements of the viral mRNA signal the ribosome to shift reading frames at a specific point. Although –1 frameshifting has been recognized since 1985, the mechanism is not well understood. I have developed a stochastic model of mRNA translation that includes the possibility of a –1 frameshift at any codon. The transition probabilities between states of the model are based on the energetics of local molecular interactions. The model reproduces observed translation rates as well as both the location and efficiency of frameshift events in the HIV-1 gag-pol sequence. In this work, the model is used to predict changes in the frameshift efficiency due to mutations in the viral mRNA sequence or variations in relative tRNA abundances. The model is sensitive to the size of the translating ribosome and to assumptions about the unfolding pathway of the stimulatory structure. As knowledge in the field of RNA structure prediction grows, that knowledge can be incorporated into the model developed here to make improved predictions. The single-ribosome translation model has been extended to polysomes by including initiation and termination rates and an exclusion principle, and allowing the stimulatory structure to refold on an appropriate timescale. The predicted frameshift efficiency for a given mRNA can be tuned by varying the ribosome density on the mRNA. This finding affects the interpretation of frameshift efficiencies measured in the lab. In the parameter regime where translation is initiation-limited, the frameshift efficiency also depends on the structure refolding rate, which determines the availability of the downstream structure for stimulating –1 frameshifts. Furthermore, there is a trade-off between frameshift efficiency and protein synthesis rate.
Type:
text; Electronic Dissertation
Keywords:
polysome; protein synthesis; ribosomal frameshift; stochastic models; translation; Applied Mathematics; elongation
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Applied Mathematics
Degree Grantor:
University of Arizona
Advisor:
Watkins, Joseph; Visscher, Koen

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleStochastic Models of –1 Programmed Ribosomal Frameshiftingen_US
dc.creatorBailey, Brenae L.en_US
dc.contributor.authorBailey, Brenae L.en_US
dc.date.issued2014-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractMany viruses can produce multiple proteins from a single mRNA sequence by encoding the proteins in overlapping genes. One mechanism that causes the ribosomes of infected cells to decode both genes is –1 programmed ribosomal frameshifting. In this process, structural elements of the viral mRNA signal the ribosome to shift reading frames at a specific point. Although –1 frameshifting has been recognized since 1985, the mechanism is not well understood. I have developed a stochastic model of mRNA translation that includes the possibility of a –1 frameshift at any codon. The transition probabilities between states of the model are based on the energetics of local molecular interactions. The model reproduces observed translation rates as well as both the location and efficiency of frameshift events in the HIV-1 gag-pol sequence. In this work, the model is used to predict changes in the frameshift efficiency due to mutations in the viral mRNA sequence or variations in relative tRNA abundances. The model is sensitive to the size of the translating ribosome and to assumptions about the unfolding pathway of the stimulatory structure. As knowledge in the field of RNA structure prediction grows, that knowledge can be incorporated into the model developed here to make improved predictions. The single-ribosome translation model has been extended to polysomes by including initiation and termination rates and an exclusion principle, and allowing the stimulatory structure to refold on an appropriate timescale. The predicted frameshift efficiency for a given mRNA can be tuned by varying the ribosome density on the mRNA. This finding affects the interpretation of frameshift efficiencies measured in the lab. In the parameter regime where translation is initiation-limited, the frameshift efficiency also depends on the structure refolding rate, which determines the availability of the downstream structure for stimulating –1 frameshifts. Furthermore, there is a trade-off between frameshift efficiency and protein synthesis rate.en_US
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectpolysomeen_US
dc.subjectprotein synthesisen_US
dc.subjectribosomal frameshiften_US
dc.subjectstochastic modelsen_US
dc.subjecttranslationen_US
dc.subjectApplied Mathematicsen_US
dc.subjectelongationen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineApplied Mathematicsen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorWatkins, Josephen_US
dc.contributor.advisorVisscher, Koenen_US
dc.contributor.committeememberWatkins, Josephen_US
dc.contributor.committeememberVisscher, Koenen_US
dc.contributor.committeememberLega, Jocelineen_US
dc.contributor.committeememberLin, Kevinen_US
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