dna; G-quadruplex; mass spectrometry; NMR; electrospray; noncovalent; ligand; spectroscopy
Abstract :
[en] Background. Guanine-rich nucleic acid sequences are capable of folding into an
intramolecular four-stranded structure called a G-quadruplex. When found in gene
promoter regions, G-quadruplexes can downregulate gene expression, possibly by
blocking the transcriptional machinery. Here we have used a genome-wide
bioinformatic approach to identify Putative G-Quadruplex Sequences (PQS) in the
Plasmodium falciparum genome, along with biophysical techniques to examine the
physiological stability of P. falciparum PQS in vitro. Results. We identified 63 PQS
in the non-telomeric regions of the P. falciparum clone 3D7. Interestingly, 16 of these
PQS occurred in the upstream region of a subset of the P. falciparum var genes
(group B var genes). The var gene family encodes PfEMP1, the parasite’s major
variant antigen and adhesin expressed at the surface of infected erythrocytes, that
plays a key role in malaria pathogenesis and immune evasion. The ability of the PQS
found in the upstream regions of group B var genes (UpsB-Q) to form stable Gquadruplex
structures in vitro was confirmed using 1H NMR, circular dichroism, UV
spectroscopy, and thermal denaturation experiments. Moreover, the synthetic
compound BOQ1 that shows a higher affinity for DNA forming quadruplex rather
than duplex structures was found to bind with high affinity to the UpsB-Q.
Conclusions. This is the first demonstration of non-telomeric PQS in the genome of
P. falciparum that form stable G-quadruplexes under physiological conditions in
vitro. These results allow the generation of a novel hypothesis that the G-quadruplex
sequences in the upstream regions of var genes have the potential to play a role in the
transcriptional control of this major virulence-associated multi-gene family.
Research Center/Unit :
Giga-Systems Biology and Chemical Biology - ULiège CART - Centre Interfacultaire d'Analyse des Résidus en Traces - ULiège
Smargiasso, Nicolas ; Université de Liège - ULiège > Département de chimie (sciences) > GIGA-R : Laboratoire de spectrométrie de masse (L.S.M.)
Gabelica, Valérie ; Université de Liège - ULiège > Département de chimie (sciences) > GIGA-R : Laboratoire de spectrométrie de masse (L.S.M.)
Damblon, Christian ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie biologique structurale
Rosu, Frédéric ; Université de Liège - ULiège > Département de chimie (sciences) > GIGA-R : Laboratoire de spectrométrie de masse (L.S.M.)
De Pauw, Edwin ; Université de Liège - ULiège > Département de chimie (sciences) > GIGA-R : Laboratoire de spectrométrie de masse (L.S.M.)
Teulade-Fichou, Marie-Paule; Institut Curie, Section Recherche, CNRS UMR176, Centre Universitaire Paris XI, Bat. 110, 91405 Orsay, France
Rowe, Jane A.; Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
Claessens, Antoine; Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
Language :
English
Title :
Putative DNA G-quadruplex formation within the promoters of Plasmodium falciparum var genes
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