TITLE:
A conformational B-Z DNA study monitored with phosphatemethylated DNA as a model for epigenetic dynamics focused on 5-(hydroxy)methylcytosine
AUTHORS:
Henk M. Buck
KEYWORDS:
B-Z DNA Transition; Artificial DNA’s; Epigenetics; Phosphorylation-Demethylation; Alzheimer
JOURNAL NAME:
Journal of Biophysical Chemistry,
Vol.4 No.2,
May
24,
2013
ABSTRACT:
This study was directed on the B- into Z-DNA isomerization with alternating CG sequences monitored
with artificial DNA model-systems based on methylation of the phosphate backbone.
The chemical concept for this transition wherein shielding of the oxygen anions
of the backbone phosphates plays an essential role, resulted in the preparation of the phosphatemethylated d(CpG). Even on this primitive level of only two base pair long, the B-Z conformational
aspects of this self-complementary duplex could be described in solution
with nuclear magnetic resonance (NMR) and circular dichroism (CD) measurements.
The exclusivity of this choice became clear after synthesizing phosphatemethylated
DNA with longer alternating CG fragments. It could be shown that conflicting
conformational effects of the CG and GC fragments resulted in an overall B
structure of the phosphatemethylated
tetramer d(CPGPCPG). From our model
considerations, it is clear that the internal stress introduced by the
alternating CG sequences will be promoted by a complete shielding of the
phosphate backbone. Elimination of this effect may be realized by a site-specific phosphate shielding. The role of the anti-syn isomerization of G in
the CG fragments is clarified by methylation of the phosphate group. This anti-syn transition is absent in
corresponding methylphosphonates, suggesting an exclusive role for
base-backbone coordination via hydrogen bonding. In addition, we propose that
the B- into Z-DNA interconversion may offer a mechanistic view for differences
in dynamics between cytosine and its epigenetic derivative 5-methylcytosine.
This mechanism has been extended to the demethylation of 5-methylcytosine and
the exchange of information
between the new epigenetic base, 5-hydroxymethylcytosine and the DNA backbone
via an intramolecular phosphorylation. The role of 5-hydroxymethylcytosine in
Alzheimer disease has been briefly discussed. In our opinion, this study
can be considered as a new dynamic concept for epigenetics based on the
dynamics of the B-Z transition in natural and phosphatemethylated DNA.