Modeling DNA Metaphase Structure Based On Loop Extrusion Model
Presentations
TU-D1030-IePD-F7-6 (Tuesday, 7/12/2022) 10:30 AM - 11:00 AM [Eastern Time (GMT-4)]
Exhibit Hall | Forum 7
Purpose: DNA geometry is complex and varied significantly at different stages of the cell cycle. To effectively quantify the ionizing radiation damage and the subsequent radiobiological effect with microscopic Monte Carlo (MC) simulation, it is critical to build DNA models representative for different cell phases. At the current stage, only DNA model at the G0/G1 cell phase was available at different MC simulation packages, which motivates us to build an effective model for other phases, like the metaphase.
Methods: The chromosomes aligned at the middle plane of the cell at the metaphase, forming dense ‘arm’ structures. The human cellular DNA contains billions of base-pairs (BPs), making it a memory disaster if loading all the coordinates of the BPs into MC simulation. Alternatively, we attempted to obtain a smallest repetitive DNA piece with the loop extrusion (LE) model. In this model, one nucleosome (containing 200 base-pairs) is taken as one monomer and the DNA ‘arm’ structure is considered a cylinder filled with polymer chain piled up around a centralized repeating spiral structure. We studied A) two-turn, B) one-turn, C) half circle of two-turn and D) a quarter circle of two-turn structure, with each turn containing 60,000 monomers. We then assessed the obtained structure with the contact probability map (PS) from experimental data.
Results: All four configurations matched well with PS from experiments under a cylindrical confinement of 209 nm in height and 352 nm in radius per turn. The density was 1 monomer per 11 nm voxel, matching the DNA density in metaphase. Reducing the structure from A) to C) and D) mainly affects the long-distance contacts, while one-turn structure dropped quickly at distance >10 million BPs.
Conclusion: Four different base DNA metaphase structures were obtained, which could be used in MC simulation for radiation-induced DNA damage computation.
Funding Support, Disclosures, and Conflict of Interest: Funding Support: 1R15CA256668-01A1
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