title: Regulation of Plasmodium falciparum Origin Recognition Complex subunit 1 (PfORC1) function through phosphorylation mediated by CDK-like kinase PK5.
abstract: Plasmodium falciparum Origin Recognition Complex subunit 1 (PfORC1) has been implicated in DNA replication and var gene regulation. While the C-terminus is involved in DNA replication, the specific role of N-terminus has been suggested in var gene regulation in a Sir2-dependent manner. PfORC1 is localized at the nuclear periphery, where the clustering of chromosomal ends at the early stage of parasite development may be crucial for the regulation of subtelomeric var gene expression. Upon disassembly of telomeric clusters at later stages of parasite development, ORC1 is distributed in the nucleus and parasite cytoplasm where it may be required for its other cellular functions including DNA replication. The level of ORC1 decreases dramatically at the late schizont stage. The mechanisms that mediate regulation of PfORC1 function are largely unknown. Here we show, by the use of recombinant proteins and of transgenic parasites expressing wild type or mutant forms of ORC1, that phosphorylation of the PfORC1-N terminal domain by the cyclin-dependent kinase (CDK) PfPK5 abolishes DNA-binding activity and leads to changes in subcellular localization and proteasome-mediated degradation of the protein in schizonts. These results reveal that PfORC1 phosphorylation by a CDK is central to the regulation of important biological functions like DNA replication and var gene silencing.
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.|National Institute of Animal Biotechnology, Hyderabad, India.
authors.forename: Abhijit S
authors.initials: AS
authors.lastname: Deshmukh
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Meetu
authors.initials: M
authors.lastname: Agarwal
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Parul
authors.initials: P
authors.lastname: Mehra
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Microbiology, School of Biomedical sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Doerig
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Suman Kumar
authors.initials: SK
authors.lastname: Dhar
mesh_terms: D000595:Amino Acid Sequence; D004261:DNA Replication; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D051738:Origin Recognition Complex / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010770:Phosphotransferases; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D052939:Schizonts / Q000502:physiology
chemical_list: D051738:Origin Recognition Complex; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D010770:Phosphotransferases