Control of plasmid DNA replication by iterons: no longer paradoxical

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Abstract
Replication origins of a family of bacterial plasmids have multiple sites, called iterons, for binding a plasmid‐specific replication initiator protein. The iteron–initiator interactions are essential for plasmid replication as well as for inhibition of plasmid over‐replication. The inhibition increases with plasmid copy number and eventually shuts plasmid replication off completely. The mechanism of inhibition appears to be handcuffing, the coupling of origins via iteron‐bound initiators that block origin function. The probability of a trans‐reaction such as handcuffing is expected to increase with plasmid copy number and diminish with increases in cell volume, explaining how the copy number can be maintained in a growing cell. Control is also exerted at the level of initiator synthesis and activation by chaperones. We propose that increases in active initiators promote initiation by overcoming handcuffing, but handcuffing dominates when the copy number reaches a threshold. Handcuffing should be ultrasensitive to copy number, as the negative control by iterons can be stringent (switch‐like).