Scaling between DNA and cell size governs bacterial growth homeostasis and resource allocation

Bacteria maintain a stable cell size and a certain DNA content through proliferation as described by classic growth laws. How cells behave when this inherent scaling is broken, however, has rarely been interrogated. Here we engineered Escherichia coli cells with extremely low DNA contents using a tunable synthetic tool CRISPRori that temporarily inhibited chromosome replication initiation. A detailed mechanistic model coupling DNA replication, cell growth, and division revealed a fundamental DNA-centric growth law, which was validated by two observations. First, lineage dynamics were robust to large CRISPRori perturbations with division cycles rapidly restoring through a timer mechanism rather than the adder rule. Second, cellular growth transitioned into a linear regime at low DNA-cytoplasm ratios. Experiments and theory showed that in this regime, cellular resource was redirected to plasmid-borne gene expression. Together with the ability of CRISPRori to bi-directionally modulate plasmid copy numbers, these findings suggest a novel strategy for bio-production enhancement.