Chromium - Induced DNA Damage and Repair - Metal Complex-DNA Interactions - page 464

lesions that may be induced by Cr(VI) exposure. It should be noted that, with the
exception of Sp and Gh, none of these other further oxidized lesions have yet been
identifi ed as arising from Cr(VI) treatment of DNA in vitro or in cellular systems.
They have, however, been identifi ed as arising in vitro in a number of other oxidizing
systems.

17.2.2 Repair of Nucleobase Damage

Repair of oxidized nucleobases is necessary to prevent the perpetuation of muta-
tions in the genetic code. Oxidized DNA lesions such as 8-oxoG and Sp are typically
repaired via the base excision repair (BER) pathway. There are several glycosylases
that have been shown to repair the oxidized nucleobase lesions induced by Cr(VI)
exposure. Table 17.2 provides a list of those glycosylases and some of the lesions
that they are known to recognize. OGG1 is a mammalian glycosylase which is a
homologue of the bacterial BER enzyme MutM and functions to repair 8-oxoG
lesions. 75 OGG1 - defi cient mice have been shown to accumulate 8-oxoG lesions over
their wild - type counterparts. 76 Another bacterial BER enzyme, endonuclease VIII
(Nei), has been recently characterized 77 and shown to repair a number of further
oxidized DNA lesions including Sp. 78 Nei defi cient Escherichia coli have been shown
to accumulate Sp lesions, but not 8-oxoG lesions 66 similar to that reported in OGG1-
defi cient mice indicating that the Nei repair enzyme is directed at the repair of these
secondary oxidation products. Recently, three mammalian homologues of the Nei
gene were identifi ed and labelled Neil1 , Neil2 and Neil3 ( Nei - like). 79,80 The NEIL1
and NEIL2 proteins were initially found to recognize cytosine-derived lesions 80 and
8-oxoG lesions present in DNA bubble structures generated during transcription
or replication. 81 Recently NEIL1 and NEIL2 have been shown to effi ciently recog-
nize the oxidized lesions Sp and Gh, but have very poor, to no, affi nity for 8-oxoG
in normal B-form DNA. 82 NEIL1 was shown to cleave Sp and Gh in both single-
and double-stranded oligonucleotides, while NEIL2 showed cleavage of Gh in both
substrates, but could not cleave Sp in double-stranded oligonucleotides. 82

Table 17.2 BER glycosylases known to repair Cr(VI) induced nucleobase lesions. Some of
these glycosylases are known to repair additional lesions not listed here but those additional
lesions have not yet been associated with Cr(VI) induced genetic damage

Prokaryotic BER glycosylase Known nucleobase substrates (for

prokaryotic BER only)

Mammalian BER
homologues a

MutM (Fpg) 8oxoG:C, Sp:C, Gh:C, 8oxoG:G,

Sp:G, Gh:G

OGG1

MutY 8oxoG:A, G:A MYH

Nei Sp:A, Gh:A, 8oxoG:C, Sp:C, Gh:

C, 8oxoG:G, Sp:G, Gh:G

NEIL1, NEIL2

a The mammalian BER homologues generally do not have as wide a range of nucleobase substrates as that of the
prokaryotic BER enzymes shown.