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Regulation of Plasmodium falciparum Origin Recognition Complex subunit 1 (PfORC1) function through phosphorylation

Abhijit S Deshmukh1,2, Meetu Agarwal1, Parul Mehra1

  • 1Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.

Molecular Microbiology
|June 23, 2015
PubMed

Insights

Phosphorylation of Plasmodium falciparum Origin Recognition Complex subunit 1 (PfORC1) by a cyclin-dependent kinase (CDK) inhibits DNA binding and triggers degradation. This regulation impacts DNA replication and var gene silencing in the parasite.

Area of Science:

  • Molecular parasitology
  • Epigenetics
  • Cell cycle regulation

Background:

  • Plasmodium falciparum Origin Recognition Complex subunit 1 (PfORC1) plays roles in DNA replication and var gene regulation.
  • PfORC1 localization shifts from the nuclear periphery to the nucleus and cytoplasm during parasite development.
  • Mechanisms regulating PfORC1 function remain largely unknown.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling PfORC1 function, particularly its N-terminal domain.
  • To elucidate the role of PfORC1 phosphorylation in its DNA-binding activity, localization, and degradation.

Main Methods:

  • Utilized recombinant proteins to study PfORC1 activity.
  • Generated transgenic parasites expressing wild-type and mutant PfORC1 forms.
  • Investigated the effect of PfPK5 (a cyclin-dependent kinase) phosphorylation on PfORC1.

Main Results:

  • Phosphorylation of the PfORC1 N-terminal domain by PfPK5 abolishes DNA-binding activity.
  • Phosphorylation induces changes in PfORC1 subcellular localization.
  • Phosphorylation leads to proteasome-mediated degradation of PfORC1 in schizonts.

Conclusions:

  • CDK-mediated phosphorylation is central to regulating PfORC1 function.
  • This phosphorylation impacts critical biological processes including DNA replication and var gene silencing.
  • Understanding PfORC1 regulation offers insights into Plasmodium falciparum biology and potential therapeutic targets.

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