title: Functional dissection of proliferating-cell nuclear antigens (1 and 2) in human malarial parasite Plasmodium falciparum: possible involvement in DNA replication and DNA damage response.
abstract: Eukaryotic PCNAs (proliferating-cell nuclear antigens) play diverse roles in nucleic acid metabolism in addition to DNA replication. Plasmodium falciparum, which causes human malaria, harbours two PCNA homologues: PfPCNA1 and PfPCNA2. The functional role of two distinct PCNAs in the parasite still eludes us. In the present study, we show that, whereas both PfPCNAs share structural and biochemical properties, only PfPCNA1 functionally complements the ScPCNA mutant and forms distinct replication foci in the parasite, which PfPCNA2 fails to do. Although PfPCNA1 appears to be the primary replicative PCNA, both PfPCNA1 and PfPCNA2 participate in an active DDR (DNA-damage-response) pathway with significant accumulation in the parasite upon DNA damage induction. Interestingly, PfPCNA genes were found to be regulated not at the transcription level, but presumably at the protein stability level upon DNA damage. Such regulation of PCNA has not been shown in eukaryotes before. Moreover, overexpression of PfPCNA1 and PfPCNA2 in the parasite confers a survival edge on the parasite in a genotoxic environment. This is the first evidence of a PfPCNA-mediated DDR in the parasite and gives new insights and rationale for the presence of two PCNAs as a parasite survival strategy and its probable success.
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Pallabi
authors.initials: P
authors.lastname: Mitra
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Khadija
authors.initials: K
authors.lastname: Banu
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Abhijit S
authors.initials: AS
authors.lastname: Deshmukh
authors.affiliation: School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Naidu
authors.initials: N
authors.lastname: Subbarao
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India skdhar2002@yahoo.co.in.
authors.forename: Suman Kumar
authors.initials: SK
authors.lastname: Dhar
mesh_terms: D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology*; D006801:Humans; D010963:Plasmodium falciparum / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry / Q000502:physiology*; D017433:Protein Structure, Secondary
chemical_list: D018809:Proliferating Cell Nuclear Antigen
keywords: DNA replication; DNA-damage response; PCNA; Plasmodium falciparum; replication foci