Abstract
Kinetoplast DNA (kDNA), a unique mitochondrial structure common to trypanosomatid parasites, contains thousands of DNA minicircles that are densely packed and can be topologically linked into a chain mail-like network. Experimental data indicate that every minicircle in the network is, on average, singly linked to three other minicircles (i.e., has mean valence 3) before replication and to six minicircles in the late stages of replication. The biophysical factors that determine the topology of the network and its changes during the cell cycle remain unknown. Using a mathematical modeling approach, we previously showed that volume confinement alone can drive the formation of the network and that it induces a linear relationship between mean valence and minicircle density. Our modeling also predicted a minicircle valence two orders of magnitude greater than that observed in kDNA. To determine the factors that contribute to this discrepancy we systematically analyzed the relationship between the topological properties of the network (i.e., minicircle density and mean valence) and its biophysical properties such as DNA bending, electrostatic repulsion, and minicircle relative position and orientation. Significantly, our results showed that most of the discrepancy between the theoretical and experimental observations can be accounted for by the orientation of the minicircles with volume exclusion due to electrostatic interactions and DNA bending playing smaller roles. Our results are in agreement with the three dimensional kDNA organization model, initially proposed by Delain and Riou, in which minicircles are oriented almost perpendicular to the horizontal plane of the kDNA disk. We suggest that while minicircle confinement drives the formation of kDNA networks, it is minicircle orientation that regulates the topological complexity of the network.
Highlights
Kinetoplastids are single cell flagellated protists that can be free living or parasitic
Mitochondrial DNA from most Kinetoplastids is composed of numerous minicircles and maxicircles with a diversity of kinetoplast DNA (kDNA) organization [4, 7, 43, 44] Interestingly, no free-living organism in the group contains a large network of topologically linked molecules [9]
The establishment of the kDNA network has been a topic of interest and various hypotheses have been proposed with confinement being the prevailing one of biophysical nature
Summary
Kinetoplastids are single cell flagellated protists that can be free living or parasitic. In our earlier work we hypothesized that volume confinement is the main contributing factor to the formation of the kDNA network To test this hypothesis, we introduced a mathematical model in which kDNA minicircles were modeled as randomly oriented geometric circles whose centers were placed on a planar square lattice grid (Fig 1B). We hypothesize that other biophysical factors, inherent to the minicircle network, may play an important role in creating a network topology simpler than expected To test this hypothesis we provide a complete quantitative characterization of the effects induced by minicircle position, bending, electrostatic repulsion and orientation on the topological properties of the kDNA network. The density of minicircles in the kDNA network of C. fasciculata is about 104.3 minicircles per squared minicircle radius
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