NCOA4 links iron bioavailability to DNA metabolism

Iron is essential for deoxyribonucleotides production and for enzymes containing an Fe-S cluster involved in DNA replication and repair. How iron bioavailability and DNA metabolism are coordinated remains poorly un-derstood. NCOA4 protein mediates autophagic degradation of ferritin to maintain iron homeostasis and in-hibits DNA replication origin activation via hindrance of the MCM2-7 DNA helicase. Here, we show that iron deficiency inhibits DNA replication, parallel to nuclear NCOA4 stabilization. In iron-depleted cells, NCOA4 knockdown leads to unscheduled DNA synthesis, with replication stress, genome instability, and cell death. In mice, NCOA4 genetic inactivation causes defective intestinal regeneration upon dextran sulfate sodium-mediated injury, with DNA damage, defective cell proliferation, and cell death; in intestinal organoids, this is fostered by iron depletion. In summary, we describe a NCOA4-dependent mechanism that coordinates iron bioavailability and DNA replication. This function prevents replication stress, maintains genome integrity, and sustains high rates of cell proliferation during tissue regeneration.

Automated summary

NCOA4 protein mediates the degradation of ferritin through autophagy to maintain iron homeostasis and inhibits the activation of DNA replication origin by hindering the MCM2-7 DNA helicase. Iron deficiency inhibits DNA replication and stabilizes nuclear NCOA4. Inactivation of NCOA4 gene in mice leads to defective intestinal regeneration, DNA damage, defective cell proliferation, and cell death.