The optimal strategy balancing risk and speed predicts DNA damage checkpoint override times.

Checkpoints arrest biological processes allowing time for error correction. The phenomenon of checkpoint override (also known as checkpoint adaptation, slippage, or leakage), during cellular self-replication is biologically critical but currently lacks a quantitative, functional, or system-level understanding. To uncover fundamental laws governing error-correction systems, we derived a general theory of optimal checkpoint strategies, balancing the trade-off between risk and self-replication speed. Mathematically, the problem maps onto the optimization of an absorbing boundary for a random walk. We applied the theory to the DNA damage checkpoint (DDC) in budding yeast, an intensively researched model checkpoint. Using novel reporters for double-strand DNA breaks (DSBs), we first quantified the probability distribution of DSB repair in time including rare events and, secondly, the survival probability after override. With these inputs, the optimal theory predicted remarkably accurately override times as a function of DSB numbers, which we measured precisely for the first time. Thus, a first-principles calculation revealed undiscovered patterns underlying highly noisy override processes. Our multi-DSB measurements revise well-known past results and show that override is more general than previously thought.