Abstract:
:Mutations of the KRAS proto-oncogene are associated with several tumor types, which is why it is being considered as a target for anti-cancer drug development. The human KRAS promoter contains a nuclease hypersensitive element (NHE), which can bind to nuclear proteins and is believed to form G-quadruplex structures. Previous studies showed that a 32-nt oligonucleotide (32R-3n) mimicking the KRAS NHE can reduce gene transcription by sequestering MAZ, a crucial transcription factor. Here we show that 32R-3n has to dimerize in order to fold into a G-quadruplex structure. Individual 5'- and 3'-end G-quadruplex units are formed and both feature a symmetric head-to-head topology with edge-type loops. The MAZ binding sequence is located within the 3'-end unit. Nuclear magnetic resonance data complemented by CD and UV spectra show that nucleotides of the MAZ binding G-rich motif are dynamic and could be available for sequence or structure based recognition. Both stable G-quadruplex structures could protect 5'- and 3'-ends of 32R-3n and enhance its anti-cancer activity. Single stranded genomic KRAS NHE including nucleotides flanking the 32R-3n sequence could favor a different monomeric fold, which remains unknown.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Podbevšek P,Plavec Jdoi
10.1093/nar/gkv1359subject
Has Abstractpub_date
2016-01-29 00:00:00pages
917-25issue
2eissn
0305-1048issn
1362-4962pii
gkv1359journal_volume
44pub_type
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