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A computational study of lambda-lac mutants
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
2009 (English)In: PHYS BIOL, ISSN 1478-3967, Vol. 6, no 4Article in journal (Refereed) Published
Abstract [en]

We present a comprehensive, computational study of the properties of bacteriophage lambda mutants designed by Atsumi and Little (2006 Proc. Natl. Acad. Sci. 103 4558-63). These phages underwent a genetic reconstruction where Cro was replaced by a dimeric form of the Lac repressor. To clarify the theoretical characteristics of these mutants, we built a detailed thermodynamic model. The mutants all have a different genetic wiring than the wild-type. lambda One group lacks regulation of P-RM by the lytic protein. These mutants only exhibit the lysogenic equilibrium, with no transiently active P-R. The other group lacks the negative feedback from CI. In this group, we identify a handful of bi-stable mutants, although the majority only exhibit the lysogenic equilibrium. The experimental identification of functional phages differs from our predictions. From a theoretical perspective, there is no reason why only 4 out of 900 mutants should be functional. The differences between theory and experiment can be explained in two ways. Either, the view of the lambda phage as a bi-stable system needs to be revised, or the mutants have in fact not undergone a modular replacement, as intended by Atsumi and Little, but constitute instead a wider systemic change.

Place, publisher, year, edition, pages
2009. Vol. 6, no 4
Keyword [en]
BACTERIOPHAGE-LAMBDA, ESCHERICHIA-COLI, CI REPRESSOR, TRANSCRIPTIONAL REGULATION, PROPHAGE INDUCTION, GENE-REGULATION, PHAGE-LAMBDA, OPERATOR DNA, CRO, BINDING
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-12092DOI: 10.1088/1478-3975/6/4/046007ISI: 000272190400007Scopus ID: 2-s2.0-70350722026OAI: oai:DiVA.org:kth-12092DiVA: diva2:301252
Note
QC20100720Available from: 2010-03-03 Created: 2010-03-03 Last updated: 2010-07-20Bibliographically approved
In thesis
1. Studies of Cellular Regulatory Mechanisms: from Genetic Switches to Cell Migration
Open this publication in new window or tab >>Studies of Cellular Regulatory Mechanisms: from Genetic Switches to Cell Migration
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cellular behaviour depends ultimately on the transcription of genes. If we know how transcription is controlled we have a better chance of understanding cellular processes. This thesis presents six studies, all concerning cellular regulatory mechanisms. One study is purely experimental and five are computational studies.

A large part of the research concerns the Epstein-Barr virus (EBV). We investigate the latency programme switching of EBV, with an equilibrium statistical mechanics model that describes the transcription activities of two central viral promoters. We demonstrate that this system is bistable and predict promoter activities that correlate well with experimental data. Further we study the switching efficiency of one of the promoters, highlighting how competitive binding of transcription factors generates a more efficient geneticswitch.

The EBV protein EBNA1 is known to affect cellular gene expression. With a dinucleotide position weight matrix we search the complete human genome for regions with multiple EBNA1 binding sites. 40 potential binding regions are identified, with several of particular interest in relation to EBV infections. The final study on EBV is purely experimental, in which we demonstrate an interaction between the Syk kinase and integrin β4. Moreover, we show how reduced levels of these proteins affect migration of epithelial LMP2a positive cells, and hypothesise that these effects are due to the Syk-β4 interaction.

The two remaining studies presented in this thesis concern other cellular systems. Dynamic properties of two different regulatory feedback mechanisms for transport and metabolism of small molecules are investigated. The synergetic effect of adding a regulatory loop is exemplified with the iron metabolism in bacteria. The final project concerns the λ phage. With the equilibrium statistical mechanics method for describing promoter activities we characterise the equilibrium properties of λ mutants and compare with experimental findings. We argue that the observed differences between model and experiment are due to a larger perturbation of the genetic circuit than presumed.

The research presented in this thesis shed light on the properties of several regulatory mechanisms. As computational studies they add perspective to the experimental research in this field and provide new hypothesis for further research.

Place, publisher, year, edition, pages
Stockholm: KTH, 2010. xiv, 80 p.
Series
Trita-CSC-A, ISSN 1653-5723 ; 2010:02
National Category
Fusion, Plasma and Space Physics
Identifiers
urn:nbn:se:kth:diva-12096 (URN)
Public defence
2010-03-18, Sal FB53, Roslagstullsbacken 21, AlbaNova, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC20100720Available from: 2010-03-03 Created: 2010-03-03 Last updated: 2010-07-20Bibliographically approved

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