Abstract
MYC, originally named c-myc, is an oncogene deregulated in many different forms of cancer. Translocation of the MYC gene to an immunoglobulin gene leads to an overexpression and the development of Burkitt’s lymphoma (BL). Sporadic BL constitutes one subgroup where one of the translocation sites is located at the 5’-vicinity of the two major MYC promoters P1 and P2. A non-B-DNA forming sequence within this region has been reported with the ability to form an intramolecular triplex (H-DNA) or a G-quadruplex. We have examined triplex formation at this site first by using a 17 bp triplex-forming oligonucleotide (TFO) and a double strand DNA (dsDNA) target corresponding to the MYC sequence. An antiparallel purine-motif triplex was detected using electrophoretic mobility shift assay. Furthermore, we probed for H-DNA formation using the BQQ-OP based triplex-specific cleavage assay, which indicated the formation of the structure in the supercoiled plasmid containing the corresponding region of the MYC promoter. Targeting non-B-DNA structures has therapeutic potential; therefore, we investigated their influence on strand-invasion of anti-gene oligonucleotides (ON)s. We show that in vitro, non-B-DNA formation at the vicinity of the ON target site facilitates dsDNA strand-invasion of the anti-gene ONs.
Highlights
DNA is a dynamic macromolecule, which can adopt various conformations
Non-B-DNA forming sequences induce genetic instability leading to mutagenic hotspots in the genome [2] such as in the MYC gene
It has been shown that a non-B-DNA structure, either H-DNA or G-quadruplex, could be formed
Summary
DNA is a dynamic macromolecule, which can adopt various conformations. The right-hand double helix B-DNA, is believed to be the most frequent structure in vivo [1]. Evidence for the possible presence of several alternative DNA conformations has emerged, such as Z-DNA, intramolecular triplex (H-DNA), cruciform and G-quadruplex These DNA structures are collectively called non-B-DNA and their implication in different biological processes, has been reported, in particular in relation to disease-associated genes. It has been shown that a non-B-DNA structure, either H-DNA or G-quadruplex, could be formed. It has been shown that a non-B-DNA structure, either H-DNA or G-quadruplex, could be formed within this sequence [13]. Both conformations are associated with blocking DNA replication and within this sequence [13]. Strand-invasion under intranuclear salt-conditions in vitro and to bind this particular site in the MYC
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