German Symposium on Systems Biology 2009, Heidelberg, Germany


Heike Hameister, Heike E. Aßmus, Alexander Skupin, Oliver Ebenhöh
A mathematical model for lagging strand synthesis and the special role of (PCNA)

The DNA replication is a fundamental process occuring in all living organisms to copy their DNA. The synthesis occurs for both strands in two different ways, this means that one of the new strand can be made continously, while the other cannot. The strand that is made continously is called the leading strand and the strand that is made discontinously is the lagging strand. The lagging strand is composed of many Okazaki fragments.

Each Okazaki fragment is initiated in eukaryotic cells near the replication fork at an RNA primer created by primase, and extended by DNA polymerase. Afterwards the polymerase binds and concludes the fragment. The primer is later removed by enzymes that have endonucleolytic activity such as the flap endonuclease FEN1. Adjoining fragments are then linked together by DNA ligase (DNA ligase 1), using phosphodiester bonds, to create a continous strand of DNA.

The mathematical model for the lagging strand synthesis is confined to the basic parameters of DNA replication (PCNA, polymerase, endonuclease FEN1 and the ligase 1). All processes of the existent model are based on elementary binding/dissociation and catalysis steps. These basic principles of enzyme kinetics can be employed for a mathematical description of the present processes of the Okazaki model.

The model allows an inspection of the different steps of DNA synthesis and to simulate the binding and unbinding of inaccurate replication proteins, as well as the drop-off of PCNA during the DNA synthesis. These occurences can decelerate the synthesis of the lagging strand or result in a collapse of the synthesis.

First results show an influence on the replication and the velocity of DNA synthesis by high total concentrations of free proteins (PCNA, polymerase, endonuclease FEN1 and the ligase 1). The concentration of the four replication proteins have been altered concurrently and the effect shows that the replication speed is not maximal for the highest total protein concentration. We can adhere to the statement, that DNA replication shows an optimum for velocity and the level raises with increasing binding specificities.

© 2009 · Heike Hameister ·