d(GC) - Association of Biotechnology and Pharmacy

Current Trends in Biotechnology and Pharmacy
Vol. 6 (2) 204-209 April 2012, ISSN 0973-8916 (Print), 2230-7303 (Online)
phosphate coordinated metal ion to N-7 of
guanosine. It is evident from the Ahmad et.al., (28)
report that the chelation via N-7 of the guanine
bases and the nearest oxygen of the (PO ) 2 - groups
prevail in Al-calf thymus DNA complexes. It has
been reported that cytosine has no major binding
site for Al. In case of Cytosine, N-1-C-6 bond of
projects onto or near to the ribose ring, and N-3 is
directed away from the phosphate moiety there by
simultaneous binding of the metal ion to phosphate
and the N-3 is not feasible and will be in anti
conformation (31). Evidence of base binding of Al
in the present investigation is also supported based
on the alterations in the CD spectra of Poly d
(GC).d(GC) and Al complex, since alterations in
CD spectra for DNA and polynucleotides have been
observed for base – binding metals (34). The
involvement of the ionic species in the interaction
of DNA is also evident from its dissociation with
native DNA regeneration upon treatment with
EDTA. Investigations carried out on chromatin from
intact nuclei of AD –affected brains offered evidence
that Al (III) markedly increased the affinity of histone
H1for DNA, thus suggesting its potential ability to
inhibit the correct gene expression in vivo (35). This
observation is interpreted as being due to the crosslinking
action of Al (III) between histones, proteins,
and DNA. The relevant bonds might involve two
carboxylate ligands pending from a histone
segment and a phosphate oxygen belonging to a
DNA nucleotide.
The ability of Al-maltol to induce Z-DNA in
poly d(GC).d(GC) might be important in chromatin
condensation and in altering the gene expressional
pattern. It is of considerable interest as biological
function is often correlated with the structure at the
molecular level. Moreover potentially Z-DNA
forming sequences are highly dispersed through
the human genome (36). It has been speculated,
based on immunohistochemical data, that Z-DNA
is about one-seventh as abundant as B-DNA (37).
In particular interest with AD, it is observed from
the Human Genome Sequence that the Z-DNA
conforming GC rich sequences are observed in
5´ regions of AD specific genes like PS1, PS2,
Govindaraju et al
207
and APOE (38). It is interesting to mention that
some of these genes have been over expressed
in AD and have significant role in AD
pathogenesis. Z-DNA formation excludes
nucleosome formation and could affect the
placement of nucleosome formation, as well as
organization of chromosomes (39) and is
considered to be involved in both transcriptional
activation and inactivation (Herbert and Rich, 1996).
It is theoretically postulated that the guanosine base
present in DNA would be more susceptible to
hydroxy radical induced DNA damage if the
conformation of the DNA is Z rather than B or A
because of the greater exposure of the bases (40).
Restriction endonucleases and methylases are
incapable of cleaving their respective recognition
sites in Z-DNA conformation (41).
Conclusion
In conclusion the GC rich regions possessing
Z-DNA conformation has great relevance to gene
expression and G* oxidation. These events like to
throw light in understanding metal induced neuronal
cell death in neurodegenerative disorder.
References
1. Crapper, D.R., Krishnan, S.S. and Dalton,
A.J. (1973). Brain aluminum distribution in
Alzheimer’s disease and experimental
neurofibrillary degeneration. Science, 180:
511-513
2. Crapper, D.R., Krishnan, S.S. and
Quittakat, S. (1976). Aluminum,
neurofibrillary degeneration and
3.
Alzheimer’s disease. Brain 99: 67-80.
Trapp, G.A., Miner, G.D., Zimmerman, R.L.,
Mastri, A.R. and Heston, L.L. (1978).
Aluminum levels in brain in Alzheimer’s
disease. Biol. Psychiatry., 13: 709-718.
4. Alfrey, A.C., LeGender, G.R. and Kaehny,
W.D. (1976). The Dialysis Encephalopathy
Syndrome — Possible Aluminum
Intoxication. N. Engl. J. Med., 294: 184 .