Chemistry Reference
In-Depth Information
A
A
A
•••ATATATAT•••
n•Hg
II
2n•H
+
T
T
T
T
Hg
II
T
T
T
T
•••TATATATA•••
A
A
A
Figure 16.7
A possible mechanism for strand slippage
: Hg
II
T-Hg
II
-T
base-pairs
n•
2n•H
+
poly-T (or T-rich) sequence
poly-dA (or A-rich) sequence
poly-dA (or A-rich) loop
Figure 16.8
A possible mechanism of deletion mutation by Hg
II
This interaction mode can rationalize the strand-slippage model for poly-
d(AT) - Hg
II
complex with a T-Hg
II
-T base pair. This is because only in the case of
the dA-dT alternating polymer [poly-d(AT)], does strand slippage by one base lead
to a continuous duplex with A-A mismatch pairs and T-Hg
II
- T base pairs (Figure
16.7). It has also been suggested that T-Hg
II
-T base pairing might be related to dele-
tion mutations when human cells are exposed to a high concentration of Hg
II
(Figure
16.8 ).
100
As a possible mechanism for this mutation, poly-d(A)-poly-d(T) sequences
might form T - Hg
II
-T base pairs within the poly-d(T) strand to give a hairpin loop.
The resulting looped-out region would be skipped by DNA polymerase during
replication of the genome. Therefore, from a toxicological point of view, the Hg
II
-
DNA interaction would be related to biological phenomena.
28,100,101
Here, we discuss the thermodynamic stability of the T-Hg
II
- T base pair. Upon
T - Hg
II
-T base pairing, the
T
m of the DNA duplex, d(CGCG
TT
GTCC)
·
d(GGAC
TT
CGCG), is considerably higher than that of the full-matched DNA duplex, d(C
GCG
TT
GTCC)
·
d(GGAC
AA
CGCG) (YT unpublished data). It was found that
the T - Hg
II
-T base pair has a similar (or higher) thermodynamic stability, relative to
Watson-Crick base pairs. Therefore, this thermodynamic stability might be a driving
force for strand slippage/displacement and loop-out. Next, we would like to note
the kinetics of T-Hg
II
-T base pairing. From NMR studies, the Hg
II
association/dis-
sociation processes in DNA duplexes have been shown generally to be slow relative
to an NMR timescale.
80 - 83
These observations are consistent with the kinetic data
from Williams and Crothers, who reported stopped-fl ow experiments with UV
spectra.
102
Therefore, once a T - Hg
II
-T base pair is formed, the pairs are not only
thermodynamically, but also kinetically, stable, suggesting that it is diffi cult to dis-
sociate T - Hg
II
-T base pairs once they are accidentally formed in cells.
For this reason, biological organisms possess a defense system against toxic
metal cations (Hg
II
, Cd
II
, Pb
II
and so on), such as metallothioneins (metal-ion-
