RecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics.
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Authors
Stanojcic, Slavica
Sterkers, Yvon
Publication Date
2018-07-02Journal Title
PLoS genetics
ISSN
1553-7390
Publisher
Public Library of Science (PLoS)
Volume
14
Issue
7
Pages
e1007490
Language
eng
Type
Article
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Claessens, A., Harris, L. M., Stanojcic, S., Chappell, L., Stanton, A., Kuk, N., Veneziano-Broccia, P., et al. (2018). RecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics.. PLoS genetics, 14 (7), e1007490. https://doi.org/10.1371/journal.pgen.1007490
Abstract
The malaria parasite Plasmodium falciparum has evolved an unusual genome structure. The
33 majority of the genome is relatively stable, with mutation rates similar to most eukaryotic
34 species. However, some regions are very unstable with high recombination rates, driving the
35 generation of new immune evasion-associated var genes. The molecular factors controlling
36 the inconsistent stability of this genome are not known. Here we studied the roles of the two
37 putative RecQ helicases in P. falciparum, PfBLM and PfWRN. When PfWRN was knocked
38 down, recombination rates increased four-fold, generating chromosomal abnormalities, a
39 high rate of chimeric var genes and many microindels, particularly in known ‘fragile sites’.
40 This is the first identification of a gene involved in suppressing recombination and
41 maintaining genome stability in Plasmodium. By contrast, no change in mutation rate
42 appeared when the second RecQ helicase, PfBLM, was mutated. At the transcriptional
43 level, however, both helicases evidently modulate the transcription of large cohorts of genes,
44 with several hundred genes – including a large proportion of vars – showing deregulated
45 expression in each RecQ mutant. Aberrant processing of stalled replication forks is a
46 possible mechanism underlying elevated mutation rates and this was assessed by
47 measuring DNA replication dynamics in the RecQ mutant lines. Replication forks moved
48 slowly and stalled at elevated rates in both mutants, confirming that RecQ helicases are
49 required for efficient DNA replication. Overall, this work identifies the Plasmodium RecQ
50 helicases as major players in DNA replication, antigenic diversification and genome stability
51 in the most lethal human malaria parasite, with important implications for genome evolution
52 in this pathogen.
Keywords
Humans, Plasmodium falciparum, Malaria, Falciparum, Genomic Instability, Protozoan Proteins, RNA, Protozoan, Antigens, Protozoan, Gene Expression Profiling, Evolution, Molecular, DNA Replication, Gene Expression Regulation, RecQ Helicases, Gene Knockdown Techniques, Whole Genome Sequencing
Sponsorship
MRC
Funder references
MRC (MR/P010873/2)
Identifiers
External DOI: https://doi.org/10.1371/journal.pgen.1007490
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279821
Rights
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/