Recombination events among virulence genes in malaria parasites are associated with G-quadruplex-forming DNA motifs

Stanton, Adam; Harris, Lynne M.; Graham, Gemma; Merrick, Catherine J.

doi:10.1186/s12864-016-3183-3

Cited by 37 publications

(105 citation statements)

References 53 publications

(93 reference statements)

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“…In bacteria, G-quadruplexes are found in Escherichia coli [161], Neisseria gonorrhoeae [162], Neisseria meningitidis [163], Mycobacterium tuberculosis [164], and Deinococcus radiodurans [165]. G-quadruplexes were also found in ciliates [14], malaria parasites [166,167], and yeasts [168,169]. Notably, helicases that resolve G-quadruplex structures, such as RecQ [170,171] and Pif1 [142] families, were found in both nonhuman and human systems.…”

Section: G-quadruplexes In Nonhuman Genomesmentioning

confidence: 99%

G-Quadruplex DNA and RNA

Yang

2019

Methods in Molecular Biology

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G-quadruplexes (G4s) have become one of the most exciting nucleic acid secondary structures. A noncanonical, four-stranded structure formed in guanine-rich DNA and RNA sequences, G-quadruplexes can readily form under physiologically relevant conditions and are globularly folded structures. DNA is widely recognized as a double-helical structure essential in genetic information storage. However, only~3% of the human genome is expressed in protein; RNA and DNA may form noncanonical secondary structures that are functionally important. G-quadruplexes are one such example which have gained considerable attention for their formation and regulatory roles in biologically significant regions, such as human telomeres, oncogene-promoter regions, replication initiation sites, and 5 0 -and 3 0 -untranslated region (UTR) of mRNA. They are shown to be a regulatory motif in a number of critical cellular processes including gene transcription, translation, replication, and genomic stability. G-quadruplexes are also found in nonhuman genomes, particularly those of human pathogens. Therefore, G-quadruplexes have emerged as a new class of molecular targets for drug development. In addition, there is considerable interest in the use of G-quadruplexes for biomaterials, biosensors, and biocatalysts. The First International Meeting on Quadruplex DNA was held in 2007, and the G-quadruplex field has been growing dramatically over the last decade. The methods used to study G-quadruplexes have been essential to the rapid progress in our understanding of this exciting nucleic acid secondary structure. G-quadruplexes have been found to form in specific human guanine-rich sequences with functional significance, such as telomeres, oncogene-promoter regions, and 5 0 -and 3 0 -untranslated region (UTR) of mRNA, as well as in nonhuman genomes. G-Quadruplexes in TelomeresThe first biologically relevant G-quadruplex was observed in telomeric DNA. Telomeres are specific DNA-protein complexes at the ends of linear chromosomes, providing protection against gene erosion from cell divisions, chromosomal nonhomologous end-joinings, and nuclease attacks [19][20][21]. Telomeric G-quadruplexes were first reported as novel intramolecular structures containing guanine-guanine base-pairs in single-stranded telomeric sequences of several organisms [22], and as guaninetetrads between hairpin loops of the Tetrahymena telomeric DNA [23]. The importance of monovalent cations in the stabilization of G-quadruplex structures was revealed by Williamson, Cech in their monovalent cation-induced square-planar G-quartet model using the Oxytricha and Tetrahymena telomeric DNA [14]. Human telomeres consist of tandem repeats of the hexanucleotide d (TTAGGG) n 5-10 kb in length, which terminate in a singlestranded 3 0 -overhang of 35-600 bases [24]. Telomeres of cancer cells do not shorten upon replication, mainly due to the activation of a reverse transcriptase, telomerase, that extends the telomeric sequence at the chromosome ends [25]. Telomerase is activated in 80-85% of hu...

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Section: G-quadruplexes In Nonhuman Genomesmentioning

confidence: 99%

G-Quadruplex DNA and RNA

Yang

2019

Methods in Molecular Biology

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“…In addition to HIV-1 evolution, other functional aspects of G4s discussed in this review, and the selective retention or exclusion of G4s from specific genomic loci in bacteria and yeast, indicate that G4s play a role in the evolution of microbes ( Figure 3) [30,[37][38][39][40][41][42].…”

Section: Recombination-[ 3 1 9 _ T D $ D I F F ] Mediated Microbial Ementioning

confidence: 92%

“…Interestingly, about a quarter of all putative quadruplex motifs in the P. falciparum genome are associated with the promoters of the var genes [29]. Stanton et al identified a close association between the recombination breakpoints and G4 motifs in P. falciparum [30]. Breakpoints were found to occur proximal to quadruplexes, especially in subtelomeic regions, indicating that G4s have a role in var-associated recombination.…”

Section: Antigenic Variationmentioning

confidence: 99%

G-Quadruplexes: More Than Just a Kink in Microbial Genomes

Saranathan

Vivekanandan

2019

Trends in Microbiology

103

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G-quadruplexes (G4s) are noncanonical nucleic acid secondary structures formed by guanine-rich DNA and RNA sequences. In this review we aim to provide an overview of the biological roles of G4s in microbial genomes with emphasis on recent discoveries. G4s are enriched and conserved in the regulatory regions of microbes, including bacteria, fungi, and viruses. Importantly, G4s in hepatitis B virus (HBV) and hepatitis C virus (HCV) genomes modulate genes crucial for virus replication. Recent studies on Epstein-Barr virus (EBV) shed light on the role of G4s within the microbial transcripts as cis-acting regulatory signals that modulate translation and facilitate immune evasion. Furthermore, G4s in microbial genomes have been linked to radioresistance, antigenic variation, recombination, and latency. G4s in microbial genomes represent novel therapeutic targets for antimicrobial therapy.

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“…falciparum. The motifs strongly associate with recombination breakpoints that were observed in var genes when parasites were cultured over many mitotic cycles, evolving new gene variants [21]. Furthermore, the knockdown of a RecQ helicase homolog called PfWRN dramatically increased the rate of var gene recombination, as would be expected if this helicase was responsible for unwinding G4s and modulating their recombinogenic effects [22].…”

mentioning

confidence: 98%

“…reichenowi, and potentially also in P. knowlesi, which has sicavar genes rather than var genes [21].…”

mentioning

confidence: 99%

Conserved associations between G-quadruplex-forming DNA motifs and virulence gene families in malaria parasites

Gage

Merrick

2020

Preprint

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Background: The Plasmodium genus of malaria parasites encodes several families of antigenencoding genes. These genes tend to be hyper-variable, highly recombinogenic and variantly expressed. The best-characterized family is the var genes, exclusively found in the Laveranian subgenus of malaria parasites infecting humans and great apes. Var genes encode major virulence factors involved in immune evasion and the maintenance of chronic infections. In the human parasite P. falciparum, var gene recombination and diversification appear to be promoted by G-quadruplex (G4) DNA motifs, which are strongly associated with var genes in P. falciparum. Here, we investigated how this association might have evolved across Plasmodium species -both Laverania and also more distantly related species which lack vars but encode other, more ancient variant gene families.Results: The association between var genes and G4-forming motifs was conserved across Laverania, spanning ~1 million years of evolutionary time, with suggestive evidence for evolution of the association occurring within this subgenus. In rodent malaria species, G4-forming motifs were somewhat associated with pir genes, but this was not conserved in the Laverania, nor did we find a strong association of these motifs with any gene family in a second outgroup of avian malaria parasites. Secondly, we compared two different G4 prediction algorithms in their performance on extremely A/T-rich Plasmodium genomes, and also compared these predictions with experimental data from G4-seq, a DNA sequencing method for identifying G4-forming motifs. We found a surprising lack of concordance between the two algorithms and also between the algorithms and G4-seq data.Conclusions: G4-forming motifs are uniquely strongly associated with Plasmodium var genes, suggesting a particular role for G4s in recombination and diversification of these genes. Secondly, in the A/T-rich genomes of Plasmodium species, the choice of prediction algorithm may be particularly influential when studying G4s in these important protozoan pathogens. BackgroundMalaria is caused by protozoan Plasmodium parasites: in humans it causes considerable morbidity and is still responsible for almost half a million deaths each year [1]. Most severe cases of human malaria are caused by Plasmodium falciparum, but a further five parasite species can infect humans 3 and there are many more species that infect rodents, birds and other vertebrates. In all vertebrate hosts, the disease involves cyclical infection of erythrocytes by Plasmodium parasites. The infected cells are exposed to circulating immune factors and also to splenic clearance, yet many malarias can lead to both chronic and repeated infections, indicating that the parasites have considerable capacities for immune evasion. These capacities have been linked, in several species, to the variant expression of virulence factors that are exposed on the infected erythrocyte surface and are encoded by highly variable families of variantly-expressed virulence genes.Such gene fa...

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Recombination events among virulence genes in malaria parasites are associated with G-quadruplex-forming DNA motifs

Cited by 37 publications

References 53 publications

G-Quadruplex DNA and RNA

G-Quadruplex DNA and RNA

G-Quadruplexes: More Than Just a Kink in Microbial Genomes

Conserved associations between G-quadruplex-forming DNA motifs and virulence gene families in malaria parasites

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