Chemistry Reference
In-Depth Information
Cells have developed a repair system for single-strand breaks that employs the same
proteins whether the damage is generated endogenously or exogenously.
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There
are four steps involved in repair of single-strand breaks: detection, end processing,
gap fi lling and ligation. Single-strand breaks are initially detected by poly (ADP-
ribose) polymerases 1 and 2, which bind to the breakage site and recruit end-
processing proteins.
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Breaks induced by high-valent chromium species have a 3
′
sugar fragment that can be removed by APE1 with the help of X-ray repair cross-
complementing protein 1 (XRCC1).
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Gap fi lling is accomplished by insertion of
a single nucleotide followed by DNA ligase sealing the nick in the sugar backbone.
17.4 Chromium - DNA Binding
17.4.1 Formation of Chromium Adducts with DNA
Chromium, whether it be in the +V, +IV or +III oxidation state, can be attracted to
the negatively charged DNA-phosphate backbone. Chromium ions may associate
themselves with DNA through initial electrostatic interactions with the phosphate
backbone that can lead to the formation of a metal-ligand complex with the phos-
phate oxygens.
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However, the metal-ligand complex formed is generally transient
in nature, as the electron lone pair necessary for coordination is shared between the
two oxygens attached to the phosphate (Figure 17.11a). This type of chromium-
DNA adduct has shown to be facile to exchange and nonmutagenic in cellular
systems.
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As such, it is likely of little importance with regard to the overall mecha-
nism of DNA damage by chromium that gives rise to carcinogenesis.
Formation of covalent bonds between chromium and the DNA nucleobases is
a more controversial proposal. A number of studies have suggested that chromium
may interact with guanine in DNA at the N7 in much the same manner as that seen
with
cis
- platinum.
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However, the lone pair of electrons at the N7 of guanine are
delocalized into the purine ring and as such, coordination at this site would not be
favoured for chromium. The unique acid/base properties, square planar geometry
and Jahn-Teller distortions associated with
cis
-platinum that allow binding at the
N7 of guanine in DNA
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do not exist with chromium. Despite DNA being a poor
ligand, some studies have shown that a portion of reduced chromium appears to
associate in a covalent manner with DNA. This binding appears only when the
reduced chromium is formed during the reduction with Cr(VI) and not through
interaction with the fi nal, stable reduced chromium oxidation state, Cr(III). This
suggests that the intermediate Cr(V) and/or Cr(IV) oxidation states of chromium
may play a role in this binding mechanism. The DNA binding interaction with
chromium has been proposed to be through the formation of ternary adducts,
(Figures 17.11 b,d).
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These ternary adducts involve bidentate chelation between the
DNA phosphate backbone and the N7 group of a guanine residue. One study has
shown that following treatment of DNA with Cr(VI) and a reductant, a large amount
of chromium was initially associated with the DNA. However, a high salt wash
removed all but 20% of the initial associated chromium. What chromium remained
