Delayed Signaling in Mitotic Checkpoints: Biological Mechanisms and Modeling Perspectives.

Time delays are intrinsic to mitotic regulation, particularly within the spindle assembly checkpoint (SAC) and the spindle position checkpoint (SPOC). These delays emerge from multi-step protein activation, molecular transport, force-dependent conformational transitions, and spatial redistribution of regulatory complexes. They span seconds to minutes and strongly influence checkpoint activation, maintenance, and silencing. Increasing evidence shows that such delayed processes shape mitotic timing, checkpoint robustness, and cell-fate decisions. While classical ordinary differential equation (ODE) models assume instantaneous biochemical responses, delay differential equations (DDEs) provide a natural framework for representing these finite timescales by explicitly incorporating system history. Recent DDE-based studies have revealed how delayed signaling contributes to bistability, oscillatory responses, prolonged mitotic arrest, and variability in checkpoint outputs. This review summarizes the biological origins of delays in SAC and SPOC, including Mad2 activation, MCC assembly and turnover, APC/C reactivation, tension maturation at kinetochores, and Bfa1-Bub2 regulation of Tem1. The article further discusses how mechanistic models with explicit delays improve our understanding of SAC-SPOC ordering, error-correction dynamics, and mitotic exit control. Finally, open challenges and future directions are outlined for integrative delay-aware modeling that unifies biochemical, mechanical, and spatial processes to better explain checkpoint function and chromosomal stability.