title: Orientation of DNA Minicircles Balances Density and Topological Complexity in Kinetoplast DNA.
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.
authors.affiliation: Department of Mathematics and Statistics, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America.
authors.forename: Yuanan
authors.initials: Y
authors.lastname: Diao
authors.affiliation: College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Victor
authors.initials: V
authors.lastname: Rodriguez
authors.affiliation: Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Klingbeil
authors.affiliation: Department of Mathematics, University of California at Davis, Davis, California, United States of America; Department of Molecular and Cellular Biology, University of California at Davis, Davis, California, United States of America.
authors.forename: Javier
authors.initials: J
authors.lastname: Arsuaga
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D016831:Crithidia fasciculata / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D018105:DNA, Kinetoplast / Q000235:genetics* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism
chemical_list: D018105:DNA, Kinetoplast; D004272:DNA, Mitochondrial