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Structure-Specific Recognition of Friedreich’s Ataxia (GAA)n Repeats by Benzoquinoquinoxaline Derivatives
Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
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2009 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 10, no 16, 2629-2637 p.Article in journal (Refereed) Published
Abstract [en]

Expansion of GAA triplet repeats in intron 1 of the FXN gene reduces frataxin expression and causes Friedreich's ataxia. (GAA)nrepeats form non-B-DNA structures, including triple helix H-DNA and higher-order structures (sticky DNA). In the proposed mechanisms of frataxin gene silencing, central unanswered questions involve the characterization of non-B-DNA structure(s) that are strongly suggested to play a role in frataxin expression. Here we examined (GAA)nbinding by triplex-stabilizing benzoquinoquinoxaline (BQQ) and the corresponding triplex-DNA-cleaving BQQ-1,10-phenanthroline (BQQ-OP) compounds. We also examined the ability of these compounds to act as structural probes for H-DNA formation within higher-order structures at pathological frataxin sequences in plasmids. DNA-complex-formation analyses with a gel-mobility-shift assay and sequence-specific probing of H-DNA-forming (GAA)nsequences by single-strand oligonucleotides and triplex-directed cleavage demonstrated that a parallel pyrimidine (rather than purine) triplex is the more stable motif formed at (GAA)nrepeats under physiologically relevant conditions.

Place, publisher, year, edition, pages
2009. Vol. 10, no 16, 2629-2637 p.
Keyword [en]
DNA cleavage, DNA, frataxin, gene expression, triplet repeat
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-56841DOI: 10.1002/cbic.200900263ISI: 000271816300011OAI: oai:DiVA.org:su-56841DiVA: diva2:413335
Available from: 2011-04-28 Created: 2011-04-28 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Development of benzoquinoquinoxaline derivatives as triplex-specific probes: Recognition of DNA structures at repeats sequences
Open this publication in new window or tab >>Development of benzoquinoquinoxaline derivatives as triplex-specific probes: Recognition of DNA structures at repeats sequences
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Repeat sequences are associated with several human diseases, such as Friedreich’s ataxia, polycystic kidney disease and cancer. These sequences can form non-B-DNA structures, including triplex (H-DNA) DNA, and are associated with genomic instability and altered gene expression. The occurrence of triplex structures in vivo and identification of their links to biological processes have been challenging. The lack of effective probes has restrained the study of triplex structures in living cells. Here, the triplex binding small molecule benzoquinoquinoxaline (BQQ) and its derivatives were developed as tools to study triplex formation at genomic repeat sequences. The triplex binding efficiency towards both purine and pyrimidine triplex motifs was determined for BQQ, the DNA cleaving BQQ-1,10-(ortho)-phenanthroline (BQQ-OP) and the fluorescent BQQ-Bodipy compounds. BQQ was shown to have the most stabilising effect on both triplex motifs. Moreover, H-DNA structure formation at a pkd1 derived sequence was demonstrated for the first time by BQQ-OP at physiologically relevant conditions. H-DNA formation was also shown at (GAA)n repeats associated with Friedreich’s ataxia and the structure was further analysed on one nucleotide resolution, confirming that (GAA)n repeats form a pyrimidine H-DNA. However, a mixture of different isomers formed at longer (GAA)n repeats. To this end, the interaction between the peptide nucleic acids (PNA) and BQQ was investigated. PNA is a DNA mimic that binds sequence-specifically to dsDNA and can form several PNA-DNA complexes. The results of PNA binding to frataxin (GAA)n expansion in plasmid were evaluated, and in the presence of GAA-PNA no triplex structure could be detected by BQQ-OP cleavage. When the structure formed in the presence of either GAA-PNA or CTT-PNA was further analysed, it was found that GAA-PNA formed a duplex invasion complex preventing H-DNA formation, whereas CTT-PNA formed a triplex invasion complex.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biology and Functional Genomics, Stockholm University, 2011. 60 p.
Keyword
Triplex, H-DNA, BQQ, BQQ-OP, BQQ-Bodipy, triplet repeat, DNA, non-B-DNA, pkd1, frataxin, Friedreich's ataxia
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-56838 (URN)978-91-7447-296-7 (ISBN)
Public defence
2011-06-01, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
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Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript.Available from: 2011-05-10 Created: 2011-04-28 Last updated: 2011-05-02Bibliographically approved

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