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Regulation of Plasmodium falciparumOrigin Recognition Complex subunit 1 (PfORC1) function through phosphorylation mediated by CDK-like kinase PK5
Deshmukh A.S., Agarwal M., Mehra P., , Gupta N., Doerig C.D., Dhar S.K.
Published in Blackwell Publishing Ltd
PMID: 26094711
Volume: 98
Issue: 1
Pages: 17 - 33
Plasmodium falciparumOrigin 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. Origin recognition complex (ORC) plays important role in eukaryotic DNA replication. Here, we demonstrate that Plasmodium falciparum ORC1 is phosphorylated at the N-terminus by CDK like kinase, PfPK5. Phosphorylation of PfORC1 leads to its compromised association with subtelomeric regions followed by cytoplasmic translocation and degradation by proteosomal pathway during the late schizont stage. These results suggest phosphorylation mediated regulation of PfORC1 required for parasite DNA replication and var gene regulation. © 2015 John Wiley & Sons Ltd.
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Published in Blackwell Publishing Ltd
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