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Title [sv]
Mekanismen med vilken leading-strand byggs
Title [en]
The mechanism of eukaryotic leading-strand DNA synthesis
Abstract [en]
Duplication of the genome before transmission to the next generation is central to life. In eukaryotes, three DNA polymerases perform this task, with DNA polymerase epsilon synthesizing the leading DNA strand. Thus, Pol epsilon synthesizes half of the DNA in your body, the total length of which corresponds to more than 50,000 round trips between the earth and the moon. DNA synthesis by Pol epsilon is fast and highly regulated and must also be accomplished with high accuracy, but our understanding of the molecular details behind these activities is still lacking. This research proposal, which is part of a long-term effort, is aimed at understanding on a structural level how Pol epsilon senses its own replication errors and corrects them, how it senses DNA lesions, how the chemical reaction is performed during DNA synthesis, and whether the redox state of an Fe-S cluster regulates the activity of Pol epsilon. To achieve this, we will use X-ray crystallography to solve a range of structures with either mutated Pol epsilon or lesions in the DNA, we will perform in crystallo reactions to visualize reaction intermediates, we will perform biochemical characterizations, including pre-steady state kinetics, and we will test models in vivo in Saccharomyces cerevisiae by using yeast genetics. What we learn in this proposal will have an impact on our general understanding of how our genome is duplicated and on the clinical interpretation of mutations that are found in cancer patients.
Principal InvestigatorJohansson, Erik
Coordinating organisation
Umeå University
Funder
Period
2018-01-01 － 2021-12-31
National Category
Biochemistry and Molecular Biology
Identifiers
DiVA, id: project:1541Project, id: 2017-04096_VR

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