Transient Zn²⁺ deficiency induces replication stress and compromises daughter cell proliferation

Cells must replicate their genome quickly and accurately, and they require metabolites and cofactors to do so. Ionic zinc (Zn²⁺) is an essential micronutrient that is required for hundreds of cellular processes, including DNA synthesis and adequate proliferation. Deficiency in this micronutrient impairs DNA synthesis and inhibits proliferation, but the mechanism is unknown. Using fluorescent reporters to track single cells via long-term live-cell imaging, we find that Zn²⁺ is required at the G1/S transition and during S phase for timely completion of S phase. A short pulse of Zn²⁺ deficiency impairs DNA synthesis and increases markers of replication stress. These markers of replication stress are reversed upon resupply of Zn²⁺. Finally, we find that if Zn²⁺ is chelated during the mother cell's S phase, daughter cells enter a transient quiescent state, maintained by sustained expression of p21, which disappears upon reentry into the cell cycle. In summary, short pulses of mild Zn²⁺ deficiency in S phase specifically induce replication stress, which causes downstream proliferation impairments in daughter cells.