Chemistry Reference
In-Depth Information
N
O
O
O
N
O
O
N
O
HN
N
Cr(V)/Cr(IV)
Cr(V)/Cr(IV)
N
N
NH
2
dR
NH
NH
NH
O
O
Spiroiminodihydantoin, Sp
N
N
NH
2
NH
2
N
N
N
NH
2
N
dR
dR
dR
Guanine
8-oxoG
Protein
or other
nucleophile
N
O
R
2
NH
O
HN
CH
N
NH
2
H
O
CH
2
N
C
dR
R
1
O
N
Guanidinohydantoin, Gh
H
N
N
O
N
N
NH
2
dR
DNA-ProteinCrosslink
Figure 17.13
Putative oxidative crosslinking mechanism showing the formation of a DNA-
protein crosslink from the guanine oxidation pathway
DNA has yet been shown, the validity of this reaction with chromium has recently
been demonstrated by Cr(V)-induced adduction of a lysine to an oxidized 8-oxoG
nucleoside.
69
17.5.2 NER and Recombination Repair of Crosslinks
Regardless of how the crosslinks are formed, they greatly alter the normal confor-
mation of B-form DNA. Such bulky lesions can prove to be lethal for the cell as
they lea,d not only to premutagenic deletions, but also to replication and transcrip-
tional blockage.
45
Nucleotide excision repair (NER) and recombination repair are
required to restore the DNA template to its undamaged form. Many protein
crosslinks recruit NER mechanisms because they only form a minor distortion of
the DNA phosphate backbone.
117,118
This is because a large proportion of the protein
crosslinks do not involve a complete protein, just individual amino acids or short
peptide chains,
119,120
creating a relatively compact lesion. These types of crosslinks
create enough distortion to recruit NER repair proteins,
45
but are not bulky enough
to require recombination repair.
There are fi ve steps involved in NER: lesion recognition, unwinding of the
damaged region, incision, excision and synthesis/ligation.
121
High - valent chromium -
induced DNA-protein crosslinks are initially identifi ed by
Xeroderma pigmentosum
group A (XPA)
122
and replication protein A (RPA),
123,124
which interact with one
another and with the DNA lesion to enhance the specifi city of lesion recognition.
125
The XPA protein will then recruit
Xeroderma pigmentosum
group B (XPB) and
