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)
First Evidence for Aluminum-maltol driven B to Z-DNA
Conformational Transition in Poly d(GC). d(GC):
Relevance to Alzheimer’s Disease
M. Govindaraju1,4 , Monica F.S. 2, 3 , Berrocal R3 ., Sambasiva Rao K.R.S. 4 and Rao K.S. 3*
1Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India
2Columbus University College of Medicine and Health Sciences, Republic Panama
3INDICASAT-AIP, City of Knowledge, Republic Panama
4Department of Biotechnology, Acharya Nagarjuna University, Guntur, India
*For Correspondence - kjr5n2009@gmail.com
Abstract
Higher concentration of Aluminum (Al)
has been observed in Alzheimer’s, Parkinson’s,
and Amyotrophic lateral sclerosis and there was
an apparent localization of the Al in chromatin in
the brain cells. Studies of Al-DNA interaction
showed that cross-linking occurs in DNAs of all
base ratios, including poly d(AT).d(AT) and poly
d(GC).d(GC). In the present investigation,
interaction of Al with poly d(GC).d(GC) and poly
d(AT).d(AT) was studied using Al-maltol, a
hydrolytically stable Al-compound, at neutral pH.
We found that Al at micromolar level caused
conformational transition from B-DNA to Z-DNA
in poly d(GC). d(GC). Chelation by EDTA could
reverse the Z-DNA caused by Al-maltol back to
+ B- DNA. We propose that Al(mal) and Al(mal)
2
2+ , major cationic species of Al-maltol at neutral
pH are involved in the above transition in poly
d(GC).d(GC). The biological relevance of DNA
transition in Alzheimer’s disease is discussed.
Key words : Aluminum maltol, DNA transition,
EDTA, Z DNA
Introduction
The interest in the biological role of
Aluminum has been stimulated by its debatable
involvement in Alzheimer’s disease (1-3), dialysis
encephalopathy (4) and ALS- Parkinson
dementia in Gaum and Kii peninsula (5-6),
204
Aluminum has been found in the nuclear region
of brain neuronal cells that contain neurofibriallry
tangles, in Alzheimer’s disease and ALS-
Parkinson dementia (7-8). Aluminum is reported
to be associated with cellular toxicity through its
interaction with DNA (9). More detailed studies
located the aluminum in the chromatin of brain
neuronal nuclei both in Alzheimer’s victims and
in animals subjected to CNS injection of
aluminum (9-12). Alzheimer’s disease is complex
neurodegenerative disorder in which etiological
factors are not clearly established although
unproven hypothesis have included trauma,
aluminum toxicity and infectious agents (13 -15).
We reported that the genomic DNA in the
hippocampus of the Alzheimer’s brain undergoes
helical transition from B-DNA to Z-DNA. We
hypothesized that aluminum, abnormal proteins
like Ab and tau, oxidative stress, and metal
homeostasis might play role in the conformational
transition (16). In the present investigation
Aluminum maltol, an Al compound was tested
for its interaction with Poly d(GC).d(GC) and Poly
d(AT).d(AT). Karlik and Eichhorn (17) reported that
interaction of Al with Poly d(GC). d(GC) using
aluminum chloride results in cross linking of DNA
by aluminum without any conformational change.
Previous studies from our lab reported that Al-maltol
could induce Z-DNA in (CCG) 12 repeats at neutral
pH (18). Since the effects of aluminum depend
First evidence for Aluminum-maltol driven B to Z-DNA