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Speed and accuracy in transcription and translation: Modelling of transcript and polypeptide elongation
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Uppsala Universitet , 2015.
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Molecular Biotechnology
Identifiers
URN: urn:nbn:se:uu:diva-262698OAI: oai:DiVA.org:uu-262698DiVA: diva2:854919
Public defence
2015-10-30, BMC A1:111a, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Knut and Alice Wallenberg FoundationVINNOVASwedish Research Council
Available from: 2015-10-08 Created: 2015-09-18 Last updated: 2015-11-23
List of papers
1. Large DNA Template Dependent Error Variation During Transcription
Open this publication in new window or tab >>Large DNA Template Dependent Error Variation During Transcription
2014 (English)In: Biophysics and Structure to Counter Threats and Challenges / [ed] Joseph D. Puglisi, Manolia V. Margaris, Springer Netherlands, 2014, , 19 p.39-57 p.Chapter in book (Other academic)
Abstract [en]

The accuracy of an enzymatic reaction system is the propensity toprocess the correct, or cognate, substrate over similar, non-cognate substrates. Thisis of particular importance to polymerization reactions with a template sequence,like transcription, translation and replication. A theoretical framework for theanalysis of accuracy control is presented, including initial substrate selection andkinetic proofreading. This framework allows for analysis not only of the efficiencyof accuracy control, but also its source in standard free energy differences andequilibrium constants and its relation to the rate of product formation. A key featureis the separation of the selection in a context dependent discard parameter anda context independent discrimination parameter. When the theory is applied tothe example of prokaryote transcription, it is shown that the discard parameter,composed by experimentally well-defined values, induces a large template sequencedependent error rate variation.

Place, publisher, year, edition, pages
Springer Netherlands, 2014. 19 p.
Series
NATO Science for Peace and Security Series B: Physics and Biophysics, ISSN 1874-6500
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Molecular Biotechnology
Identifiers
urn:nbn:se:uu:diva-181002 (URN)10.1007/978-94-007-4923-8_3 (DOI)978-94-007-4922-1 (ISBN)
Conference
Biophysics and Structure to Counter Threats and Challenges
Funder
VINNOVA
Available from: 2012-09-14 Created: 2012-09-14 Last updated: 2015-10-20
2. Thermodynamic Modeling of Variations in the Rate of RNA Chain Elongation of E-coli rrn Operons
Open this publication in new window or tab >>Thermodynamic Modeling of Variations in the Rate of RNA Chain Elongation of E-coli rrn Operons
2014 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 1, 55-64 p.Article in journal (Refereed) Published
Abstract [en]

Previous electron-microscopic imaging has shown high RNA polymerase occupation densities in the 16S and 23S encoding regions and low occupation densities in the noncoding leader, spacer, and trailer regions of the rRNA (rrn) operons in E. coli. This indicates slower transcript elongation within the coding regions and faster elongation within the noncoding regions of the operon. Inactivation of four of the seven rrn operons increases the transcript initiation frequency at the promoters of the three intact operons and reduces the time for RNA polymerase to traverse the operon. We have used the DNA sequence-dependent standard free energy variation of the transcription complex to model the experimentally observed changes in the elongation rate along the rrnB operon. We also model the stimulation of the average transcription rate over the whole operon by increasing rate of transcript initiation. Monte Carlo simulations, taking into account initiation of transcription, translocation, and backward and forward tracking of RNA polymerase, partially reproduce the observed transcript elongation rate variations along the rrn operon and fully account for the increased average rate in response to increased frequency of transcript initiation.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-217653 (URN)10.1016/j.bpj.2013.11.4487 (DOI)000329407700010 ()
Available from: 2014-02-12 Created: 2014-02-04 Last updated: 2017-12-06Bibliographically approved
3. DNA Template Dependent Accuracy Variation of Nucleotide Selection in Transcription
Open this publication in new window or tab >>DNA Template Dependent Accuracy Variation of Nucleotide Selection in Transcription
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, e0119588Article in journal (Refereed) Published
Abstract [en]

It has been commonly assumed that the effect of erroneous transcription of DNA genes into messenger RNAs on peptide sequence errors are masked by much more frequent errors of mRNA translation to protein. We present a theoretical model of transcriptional accuracy. It uses experimentally estimated standard free energies of double-stranded DNA and RNA/DNA hybrids and predicts a DNA template dependent transcriptional accuracy variation spanning several orders of magnitude. The model also identifies high-error as well a high-accuracy transcription motifs. The source of the large accuracy span is the context dependent variation of the stacking free energy of pairs of correct and incorrect base pairs in the ever moving transcription bubble. Our model predictions have direct experimental support from recent single molecule based identifications of transcriptional errors in the C. elegans transcriptome. Our conclusions challenge the general view that amino acid substitution errors in proteins are mainly caused by translational errors. It suggests instead that transcriptional error hotspots are the dominating source of peptide sequence errors in some DNA template contexts, while mRNA translation is the major cause of protein errors in other contexts.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-252228 (URN)10.1371/journal.pone.0119588 (DOI)000351987300062 ()25799551 (PubMedID)
Funder
VINNOVAWenner-Gren FoundationsKnut and Alice Wallenberg Foundation
Available from: 2015-05-06 Created: 2015-05-04 Last updated: 2017-12-04Bibliographically approved
4. Transcriptional accuracy modelling suggests two-step proofreading by RNA polymerase
Open this publication in new window or tab >>Transcriptional accuracy modelling suggests two-step proofreading by RNA polymerase
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Molecular Biotechnology
Identifiers
urn:nbn:se:uu:diva-262692 (URN)
Available from: 2015-09-18 Created: 2015-09-18 Last updated: 2015-10-20
5. The influence of ribosome queuing on fusidic acid inhibition of translocation in translation
Open this publication in new window or tab >>The influence of ribosome queuing on fusidic acid inhibition of translocation in translation
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Molecular Biotechnology
Identifiers
urn:nbn:se:uu:diva-262693 (URN)
Available from: 2015-09-18 Created: 2015-09-18 Last updated: 2015-10-20
6. Global aspects of the translational accuracy of the genetic code predicted from the accuracy of codon reading by a subset of transfer RNAs
Open this publication in new window or tab >>Global aspects of the translational accuracy of the genetic code predicted from the accuracy of codon reading by a subset of transfer RNAs
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Molecular Biotechnology
Identifiers
urn:nbn:se:uu:diva-262694 (URN)
Available from: 2015-09-18 Created: 2015-09-18 Last updated: 2015-10-20

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