Chemistry Reference
In-Depth Information
30 proteins are involved (recently summarized in references 108 and 118). In the
fi rst stage, arsenite seems to disturb the DNA damage recognition/incision step, but
effects on DNA ligation are observed as well
113
One possible mechanism of arsenic-induced toxicity may lie in its ability to
react with thiols, for example in zinc-binding structures prevalent in many transcrip-
tion factors, cell cycle control and DNA repair proteins (recently reviewed in
reference 119). In case of the central NER DNA damage recognition protein XPA,
trivalent arsenicals have been shown to release zinc from a 37 amino acid XPAzf
peptide, representing the zinc-fi nger domain of the human XPA protein.
42
Thus
equimolar MMA
III
released Zn
II
easily, forming mono- and diarsenical derivatives
of XPAzf.
120
In contrast, a 10-fold excess of arsenite was required to partially oxidize
the zinc - fi nger structure of XPAzf. Thus, zinc-binding structures may be sensitive
targets for arsenicals, even though the actual species involved in the specifi c interac-
tion differ. With respect to XPA function, subcellular studies observed no or only a
slight decrease on XPA binding to UVC-
121
or MMC - damaged
122
oligonucleotides
by arsenite.
To date the most sensitive target related to DNA repair is inhibition of
poly(ADP-ribosyl)ation by trivalent arsenicals at nanomolar concentrations, with
MMA
III
and DMA
III
showing the strongest effects.
123,124
Poly(ADP - ribosyl)ation,
which is mediated mainly by the poly(ADP-ribose) polymerase 1 (PARP-1), plays
a major role in DNA damage signalling and the recruitment of DNA repair proteins
to sites of damage. Although the role of PARP-1 is not fully understood as yet, there
is strong evidence that PARP-1 contributes to base excision repair (BER),
125
which
among others is responsible for the repair of oxidative DNA damage, and perhaps
also to NER. In this context, Poonepalli
et al.
reported that in mouse embryonic
fi broblasts, a lack of PARP-1 gene product enhances cellular sensitivity to arsen-
ite.
126
With respect to BER, arsenite has also been shown to inhibit DNA ligase
III activity in cells and nuclear extracts, most probably indirectly by altering
cellular redox levels or by affecting signal transduction pathways related to ligase
activity.
127,128
As mentioned before, effects on the tumour suppressor protein p53 may also
contribute to arsenic-induced carcinogenicity. Following activation by posttransla-
tional modifi cations such as phosphorylation, acetylation and poly(ADP - ribosyl)ation,
p53 plays a guarding role in maintaining genome integrity by activating the tran-
scription of genes involved in cell cycle check points, cellular senescence, apoptosis
and DNA repair (e.g.,
XPC, p48, hOGG1
). At present effects of arsenic on p53 are
not well understood, since responses are different depending on cell type and incu-
bation times. Investigations in human fi broblasts and human lymphoblastoid cell
lines have identifi ed that arsenite could induce p53 accumulation through an ATM-
dependent pathway.
129,130
On the other hand, arsenite and MMA
III
have been shown
to inhibit p53 phosphorylation and to reduce overall p53 level, as well as p53 DNA-
binding activity.
116,131
Furthermore a recent study has postulated increased formation
of conformationally mutated p53 by arsenite.
132
Due to the loss of its zinc-containing
folded wild-type conformation, this conformationally mutated p53 is no longer
capable of function as a transcription factor;
133,134
many cancer - associated mutations
cause loss of this conformation.
135
