title: The role of N-terminus of Plasmodium falciparum ORC1 in telomeric localization and var gene silencing.
abstract: Plasmodium falciparum origin recognition complex 1 (ORC1) protein has been implicated in DNA replication and silencing var gene family. However, the mechanism and the domain structure of ORC1 related to the regulation of var gene family are unknown. Here we show that the unique N-terminus of PfORC1 (PfORC1N(1-238)) is targeted to the nuclear periphery in vivo and this region binds to the telomeric DNA in vitro due to the presence of a leucine heptad repeats. Like PfORC1N(1-238), endogenous full length ORC1, was found to be associated with sub telomeric repeat regions and promoters of various var genes. Additionally, binding and propagation of ORC1 to telomeric and subtelomeric regions was severely compromised in PfSir2 deficient parasites suggesting the dependence of endogenous ORC1 on Sir2 for var gene regulation. This feature is not previously described for Plasmodium ORC1 and contrary to yeast Saccharomyces cerevisiae where ORC function as a landing pad for Sir proteins. Interestingly, the overexpression of ORC1N(1-238) compromises the binding of Sir2 at the subtelomeric loci and var gene promoters consistent with de-repression of some var genes. These results establish role of the N-terminus of PfORC1 in heterochromatin formation and regulation of var gene expression in co-ordination with Sir2 in P. falciparum.
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Abhijit S
authors.initials: AS
authors.lastname: Deshmukh
authors.forename: Sandeep
authors.initials: S
authors.lastname: Srivastava
authors.forename: Susann
authors.initials: S
authors.lastname: Herrmann
authors.forename: Ashish
authors.initials: A
authors.lastname: Gupta
authors.forename: Pallabi
authors.initials: P
authors.lastname: Mitra
authors.forename: Tim Wolf
authors.initials: TW
authors.lastname: Gilberger
authors.forename: Suman Kumar
authors.initials: SK
authors.lastname: Dhar
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D020868:Gene Silencing; D051738:Origin Recognition Complex / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D010963:Plasmodium falciparum / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015800:Protozoan Proteins / Q000235:genetics*; D020449:Repetitive Sequences, Amino Acid; D012091:Repetitive Sequences, Nucleic Acid; D056565:Sirtuin 2 / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*
chemical_list: D051738:Origin Recognition Complex; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D004247:DNA; D056565:Sirtuin 2