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C8‐Arylguanine modified oligonucleotides: Tools for investigating Z‐DNA formation
Author(s) -
Train Brian Christopher,
Vongsutilers Vorasit,
Thomsen Nissa M.,
Gannett Peter M.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.762.2
Subject(s) - dna , oligonucleotide , chemistry , z dna , hmg box , mutagenesis , biophysics , gene , biochemistry , dna binding protein , mutation , biology , transcription factor
DNA has many different conformations however only Z‐DNA adopts a left‐handed helix. The zigzag phosphate backbone of Z‐DNA brings the negatively charged phosphate residues closer together rendering Z‐DNA a higher energy form of DNA. Z‐DNA has been implicated in carcinogenesis from its role in gene expression and mutagenesis because Z‐DNA formation can stimulate large scale gene deletions, translocations, and rearrangements in vivo . The inability to generate a stable Z‐DNA structure under physiological conditions has made investigation of B‐ to Z‐DNA interconversion difficult since Z‐DNA requires external stimuli to stabilize its formation like chemical modifications or specific proteins known to stabilize Z‐DNA, Z‐DNA binding proteins (ZBP). We have demonstrated that C8‐arylguanine DNA adducts, derived from carcinogenic arylhydrazines, drive Z‐DNA formation and the addition of MgCl 2 stabilizes the Z form under physiological conditions. The conformational effects of the C8‐arylguanine mutation were determined by nuclear magnetic resonance (NMR) and circular dichroism (CD). In addition, preliminary results using in silico molecular dynamics and CD have demonstrated that ZBPs prefer to bind to the C8‐arylguanine modified DNA. C8‐Arylguanine can be used as a tool to clarify the mechanism of ZBP mediated B‐ to Z‐DNA transition. The current view fails to explain the ZBP selectivity for the Z form and leads to a contradictory conclusion that ZBPs cannot bind Z‐DNA. C8‐Arylguanine modified oligonucleotides can be used to fully elucidate the binding of ZBPs to DNA, as both the B and Z forms can be generated under physiological conditions, using surface plasmon resonance (SPR). This may reveal the underlying factors that control ZBP‐DNA interactions which could become a potential therapeutic target. (Supported by a fellowship to BCT (HEPC.dsr.09013) and (NSF EPS‐1003907)