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The apicoplast of Plasmodium falciparum carries a 35 kb circular genome (plDNA) that replicates at the late trophozoite stage of the parasite intraerythocytic cycle. plDNA replication proceeds predominantly via ad-loop/bi-directional ori mechanism with replication ori localized within inverted repeat region. Although replication of the apicoplast genome is a validated drug target, the proteins involved in the replication process are only partially characterized. We analysed DNA–protein interactions at a plDNA replication ori region and report the identification of a nuclear-encoded DnaJ homologue that binds directly to ori elements of the plDNA molecule. PfDnaJA interacted with the minor groove of the DNA double-helix and recognized a 13 bp sequence within the ori. Inhibition of binding with anti-PfDnaJA antibodies confirmed identity of the protein in DNA-binding experiments with organellar protein fractions. The DNA-binding domain of the ∼69 kDa PfDnaJA lay within the N-terminal 38 kDa region that carries DnaJ signature motifs. In contrast to PfDnaJA in parasite organellar fractions, the recombinant protein interacted with DNA in a sequence non-specific manner. Our results suggest a role for PfDnaJA in replication/repair of the apicoplast genome. [ABSTRACT FROM AUTHOR]