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dc.contributor.authorClaessens, Antoine
dc.contributor.authorHarris, Lynne M
dc.contributor.authorStanojcic, Slavica
dc.contributor.authorChappell, Lia
dc.contributor.authorStanton, Adam
dc.contributor.authorKuk, Nada
dc.contributor.authorVeneziano-Broccia, Pamela
dc.contributor.authorSterkers, Yvon
dc.contributor.authorRayner, Julian
dc.contributor.authorMerrick, Catherine
dc.date.accessioned2018-09-08T06:31:31Z
dc.date.available2018-09-08T06:31:31Z
dc.date.issued2018-07
dc.identifier.issn1553-7390
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/279821
dc.description.abstractThe 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.
dc.description.sponsorshipMRC
dc.format.mediumElectronic-eCollection
dc.languageeng
dc.publisherPublic Library of Science (PLoS)
dc.rightsAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHumans
dc.subjectPlasmodium falciparum
dc.subjectMalaria, Falciparum
dc.subjectGenomic Instability
dc.subjectProtozoan Proteins
dc.subjectRNA, Protozoan
dc.subjectAntigens, Protozoan
dc.subjectGene Expression Profiling
dc.subjectEvolution, Molecular
dc.subjectDNA Replication
dc.subjectGene Expression Regulation
dc.subjectRecQ Helicases
dc.subjectGene Knockdown Techniques
dc.subjectWhole Genome Sequencing
dc.titleRecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics.
dc.typeArticle
prism.issueIdentifier7
prism.publicationDate2018
prism.publicationNamePLoS Genet
prism.startingPagee1007490
prism.volume14
dc.identifier.doi10.17863/CAM.27191
dcterms.dateAccepted2018-06-13
rioxxterms.versionofrecord10.1371/journal.pgen.1007490
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-07-02
dc.contributor.orcidClaessens, Antoine [0000-0002-4277-0914]
dc.contributor.orcidHarris, Lynne M [0000-0001-7310-8504]
dc.contributor.orcidStanton, Adam [0000-0003-3865-2381]
dc.contributor.orcidVeneziano-Broccia, Pamela [0000-0002-3498-7304]
dc.contributor.orcidRayner, Julian [0000-0002-9835-1014]
dc.contributor.orcidMerrick, Catherine [0000-0001-7583-2176]
dc.identifier.eissn1553-7404
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/P010873/2)
cam.issuedOnline2018-07-02


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)