Cell cycle is a process and function of a cell with different phases essential for cell growth, proliferation, and replication. Cell cycle depends on the structure and dynamics of the underlying DNA molecule, which underpins the genome function. A microscopic structural-level understanding of how genome or its functional module chromosome performs the cell cycle in terms of large-scale conformational transformation between different phases such as the interphase and the mitotic phase is still challenging. Here, we develop a non-equilibrium excitation-relaxation energy landscape-switching model to quantify the underlying chromosome conformational transitions through (de-)condensation for a complete microscopic understanding of the cell cycle. We show that the chromosome conformational transition mechanism from the interphase to the mitotic phase follows a two-stage scenario, in good agreement with the experiments. In contrast, the mitotic exit pathways show the existence of an over-expanded chromosome that recapitulates the chromosome in the experimentally identified intermediate state at the telophase. We find the conformational pathways are heterogeneous and irreversible, as a result of the non-equilibrium dynamics of the cell cycle from both structural and kinetic perspectives. We suggest that the irreversibility is mainly due to the distinct participation of the ATP-dependent structural maintenance of chromosomal protein complexes during the cell cycle. Our findings provide crucial insights into the microscopic molecular structural and dynamical physical mechanism for the cell cycle beyond the previous more macroscopic descriptions. Our non-equilibrium landscape framework is general and applicable to study diverse non-equilibrium physical and biological processes such as active matter, differentiation/development and cancer. ### Competing Interest Statement The authors have declared no competing interest.
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