RecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics

Abstract

The malaria parasite Plasmodium falciparum has evolved an unusual genome structure. The majority of the genome is relatively stable, with mutation rates similar to most eukaryotic species. However, some regions are very unstable with high recombination rates, driving the generation of new immune evasion-associated var genes. The molecular factors controlling the inconsistent stability of this genome are not known. Here we studied the roles of the two putative RecQ helicases in P. falciparum, PfBLM and PfWRN. When PfWRN was knocked down, recombination rates increased four-fold, generating chromosomal abnormalities, a high rate of chimeric var genes and many microindels, particularly in known ‘fragile sites’. This is the first identification of a gene involved in suppressing recombination and maintaining genome stability in Plasmodium. By contrast, no change in mutation rate appeared when the second RecQ helicase, PfBLM, was mutated. At the transcriptional level, however, both helicases evidently modulate the transcription of large cohorts of genes, with several hundred genes—including a large proportion of vars—showing deregulated expression in each RecQ mutant. Aberrant processing of stalled replication forks is a possible mechanism underlying elevated mutation rates and this was assessed by measuring DNA replication dynamics in the RecQ mutant lines. Replication forks moved slowly and stalled at elevated rates in both mutants, confirming that RecQ helicases are required for efficient DNA replication. Overall, this work identifies the Plasmodium RecQ helicases as major players in DNA replication, antigenic diversification and genome stability in the most lethal human malaria parasite, with important implications for genome evolution in this pathogen.

Publication DOI: https://doi.org/10.1371/journal.pgen.1007490
Additional Information: © 2018 Claessens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The work was supported by the UK Medical Research Council [grants MR/K000535/1 and MR/L008823/1 to CJM], the Wellcome Trust [grant 090851 to JCR], the Agence Nationale de la Recherche within the frame of the “Investissements d’avenir” program [ANR-11-LABX-0024-01 “PARAFRAP” to YS], the Centre National de la Recherche Scientifique (CNRS), the French Ministry of Research and the Centre Hospitalier Universitaire of Montpellier [YS], and the ‘Fondation pour la Recherche Médicale’ (FRM) [SS]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publication ISSN: 1553-7404
Last Modified: 03 Jan 2024 08:15
Date Deposited: 09 Sep 2022 07:28
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Related URLs: https://journal ... al.pgen.1007490 (Publisher URL)
PURE Output Type: Article
Published Date: 2018-07-02
Accepted Date: 2018-06-13
Authors: Claessens, Antoine
Harris, Lynne M.
Stanojcic, Slavica
Chappell, Lia
Stanton, Adam
Kuk, Nada
Veneziano-Broccia, Pamela
Sterkers, Yvon
Rayner, Julian C.
Merrick, Catherine J.

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