DNA Replication Asymmetry and Proteostasis Collapse Dynamics

Replication fidelity differs across leading and lagging strands and between early- and late-replicating genomic regions, generating asymmetric mutational inputs across proliferative lineages. How such asymmetries influence long-term proteostasis stability has not been quantitatively evaluated. Here, we develop a stochastic generational model linking replication-derived mutation asymmetry to proteotoxic load dynamics under age-dependent declines in clearance. Mutations are drawn from symmetric (H0) or strand- and timing-asymmetric (H1) Poisson processes, converted into proteotoxic load through a binomial misfolding mechanism, and cleared with linearly declining proteostasis efficiency. Proteostasis collapse is defined as a first-passage event when total load exceeds a capacity threshold. Across homeostatic and near-failure regimes, replication asymmetry modestly increases steady-state proteotoxic load (approximately 1– 3%) and leads to modestly earlier collapse. Under clearance-compromised or stress-test conditions, asymmetry substantially amplifies collapse probability and accelerates failure. These results demonstrate that replication-associated asymmetry acts as a weak perturbation when basal load dominates but becomes a significant modifier of collapse risk when proteostasis capacity is reduced. The framework provides a quantitative basis for evaluating how replication dynamics shape long-term proteostasis stability in proliferative tissues.