Chemistry Reference
In-Depth Information
Xeroderma pigmentosum
group D (XPD) helicases to unwind the DNA surround-
ing the damaged site. XPB will unwind the DNA in the 3
′
to 5
′
direction
126
and XPD
will unwind the DNA in the 5
direction
127
from the site of the lesion. Once the
DNA has been unwound, a patch of DNA
′
to 3
′
∼
25-30 base pairs in length can be
cleaved. The fi rst incision is made on the 3
side of the lesion by
Xeroderma pigmen-
tosum
group G (XPG) endonuclease.
128,129
This incision is made
′
∼
3 - 5 base pairs to
the 3
incision can
be made.
131
Excision repair cross-complementing 1 (ERCC1) and 4 (ERCC4) pro-
teins will then form a complex and cleave the DNA phosphate backbone
′
side of the lesion
130,131
and is required to be completed before a 5
′
∼
22 - 25
base pairs to the 5
side of the lesion.
129,130,132
RPA remains bound throughout the
incision step because it is required for facilitating release of the excised oligonucle-
otide.
120
Following release of the oligonucleotide, proliferating cell nuclear antigen
(PCNA) displaces the incision proteins,
130
clearing the way for polymerase d or
polymerase e to synthesize a new segment of DNA.
131
The nicks in the phosphate
backbone are then sealed by DNA ligase.
Chromium-induced DNA crosslinks, as well as protein crosslinks involving a
complete protein are thought to be the primary lesions obstructing DNA replication
past guanine residues.
132 - 134
Treatment of mammalian cells with nonlethal concentra-
tions of Cr(VI) has been shown to greatly enhance recombination,
135
lending support
to the proposal that these types of crosslinks do form in cellular systems following
Cr(VI) exposure. When a polymerase encounters one of these bulky chromium-
induced lesions, it will stall, causing the replication fork to collapse.
136
Collapse of a
replication fork creates a single-ended double-strand break.
137
A variation of homol-
ogous recombination repair called replication fork repair is used to mend double-
strand breaks created by the collapse of a replication fork.
138
As a side note,
replication fork collapse can also be induced by the presence of an unrepaired
single - strand break
139
or by the presence of a rigid oxidized nucleobase lesion.
96
Oxidation of the deoxyribose by high-valent chromium ions, as well as formation
of secondary oxidative guanine lesions like Sp could thus trigger replication fork
collapse if the subsequent single-strand breaks are not promptly repaired. Homolo-
gous recombination repair is also referred to as error-free repair,
137
making it the
most favourable form of recombination for repair of exogenous DNA damage.
However, in the replication fork repair version of homologous recombination, sister
chromatid exchanges can potentially arise if the leading strand template becomes
covalently attached to the daughter lagging strand.
139,140
Chromium compounds have
been shown to induce sister chromatid exchanges,
47 - 49
which may be partially attrib-
uted to homologous recombination repair following the collapse of replication forks
at chromium-induced DNA and protein crosslinks.
′
17.6 Conclusions
Even though chromium has been one of the most extensively researched metal
carcinogens, there is still much that is not known about its fundamental mechanism
of interaction with DNA. This current lack of understanding is due to the complexity
