The iron-sulfur accelerator YgfZ modulates genome-wide IHF-binding dynamics to regulate replication initiation in...

In Escherichia coli, chromosome replication is regulated through ATP/ADP state of the DnaA initiator. The DDAH system inactivates DnaA in the post-initiation stage by promoting ATP hydrolysis through timely binding of the DNA-bending protein IHF to the datA locus, while the DARS2 locus reactivates DnaA in the pre-initiation stage via binding of IHF and another nucleoid protein Fis. The iron-sulfur cluster [(Fe-S)] assembly factor YgfZ is known to sustain replication initiation, central carbon metabolism, redox state and modification of tRNA A37 residues by MiaB, but the link between initiation and the others remains unclear. This study shows that YgfZ regulates initiation primarily by downregulating the DDAH system by repressing datA-IHF binding in a manner independent of MiaB. Also, the [Fe-S]-binding protein MnmA moderately downregulates datA-IHF binding. Furthermore, YgfZ globally downregulates basal IHF binding across the genome, while preserving IHF's timely binding at key loci including oriC and datA during the cell cycle, highlighting a novel strategy: YgfZ modulates both the cellular metabolic states and global genome dynamics to control replication initiation under various growth conditions.