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From the Laboratory of Molecular Genetics, NIA, National
Institutes of Health, Baltimore, Maryland 21224
INTRODUCTION Reactive oxygen species
(ROS)1 are generated in cells
as a by-product of cellular metabolism. ROS react with proteins,
lipids, and DNA. DNA base modifications, abasic sites, deoxyribose
damage, and single and double strand breaks are all induced following various forms of oxidative stress. This review will focus on DNA repair
of oxidative lesions by base excision repair (BER) and nucleotide
excision repair (NER). We will focus on the mammalian BER enzymes that
have recently been cloned and characterized. Mitochondrial DNA repair
mechanisms for oxidative damage will also be discussed. Although sugar
damage and double strand breaks are critical lesions induced by
ionizing radiation and bleomycin, repair of these lesions will not be
discussed here (see Refs. 1-3 for recent reviews).
Oxidative DNA Damage and Its Consequences The endogenous attack on DNA by ROS species generates a low
steady-state level of DNA adducts that have been detected in the DNA
from human cells (4). Some of these base modifications are shown in
Fig. 1. There are many more, and it is
possible that the full spectrum of oxidative lesions in endogenous
mammalian DNA exceeds 100 different types, of which 8-hydroxyguanine
(8-oxoG) is one of the most abundant (5).
Oxidative DNA damage is thought to contribute to carcinogenesis, aging,
and neurological degeneration (for reviews, see Refs. 5 and 6). Studies
have shown that oxidative DNA damage accumulates in cancerous tissue.
For example, higher levels of oxidative base damage were observed in
lung cancer tissue compared with surrounding normal tissue (7). Another
study reported a 9-fold increase in 8-oxoG, 8-hydroxyadenine, and
2,6-diamino-4-hydroxy-5-formamidopyrimidine in DNA from breast cancer
tissue compared with normal tissue (8). Further, the cumulative risk of
cancer increases dramatically with age in humans (9), and cancer can in
general terms be regarded as a degenerative disease of old age. There
is evidence for the accumulation of oxidative DNA damage with age based
on studies mainly measuring the increase in 8-oxoG (10). In
Alzheimer's disease (AD), some studies have shown an accumulation of
oxidative DNA damage in the brain, and a recent extensive study in
cells from familial Alzheimer's disease demonstrated a deficiency in the processing of damage invoked by fluorescent light (11). The effects
of fluorescent light exposure were inhibited by the addition of free
radical scavengers, and therefore it was proposed that oxidative DNA
damage was produced and responsible for the altered response seen in AD
cells (11). AD cells also respond abnormally to ionizing radiation and
simple alkylating agents, and therefore it is possible that lesions
introduced by these agents such as oxidative modifications,
alkylpurines, or DNA strand breaks are not repaired efficiently in
AD cells (12).
Many experimental methods have been used to expose cells to
oxidative damage, all attempting to mimic endogenous processes (4, 6). Some studies have used hydrogen peroxide, which generates a
large spectrum of lesions. Ionizing radiation also generates a wide
spectrum of lesions including base damage and single and double strand
breaks in DNA. Methylene blue plus visible light exposure primarily
generates singlet oxygen damage, and osmium tetroxide generates
primarily thymine glycols. For more discussion of this see Refs. 4 and
6. It is important to distinguish between the different types of
oxidative stresses when evaluating experimental results.
Technical differences in the methods used for DNA isolation may well
result in differences in the analysis of the DNA adducts. A recent
review compared the various methods used to detect oxidative damage in
DNA (13). One of the conclusions that emerged from the comparison was
that there is a great need for methods to be more standardized and thus
to provide more consistent results between different laboratories when
comparing different but related techniques.
One aspect that is common to many methods used to detect oxidative
damage is that the DNA modifications are measured as averages in the
total cellular DNA. This is of limited value since advances in recent
years have shown that DNA damage processing and the biological
consequences of DNA lesions vary considerably depending upon where a
lesion is situated in the genome. For example, UV-induced photoproducts
are processed differently whether situated in an active gene or in a
non-transcribed region, and this may also be the case for oxidative
lesions.
The gene-specific repair assay (GSR) employs various DNA repair enzymes
to detect specific lesions, and this assay has provided new insights
about the heterogeneity of DNA repair in the nucleus (14) and more
recently about the repair mechanisms for mitochondrial DNA (see below).
For example, endonuclease III (endo III) can detect oxidized
pyrimidines, and the Fapy DNA glycosylase (Fpg protein) can detect
oxidized purines. Endo III-sensitive sites have been assayed in the
general genome (15), and more recently, Fpg protein has been used to
detect lesions in specific genes (16, 17).
Base Excision Repair of Oxidative Damage BER is initiated by DNA glycosylases, a class of enzymes that
recognize a specific set of modified bases such as 8-oxoG or thymine
glycol (TG). Glycosylases cleave the N-glycosylic bond between the modified base and the sugar. There are two classifications of glycosylases: simple glycosylases that only cleave the
N-glycosylic bond and glycosylase/AP lyase enzymes, which
cleave the N-glycosylic bond and the DNA-phosphate backbone.
Following the glycosylase step, AP endonucleases are required to remove
the 3 The majority of our knowledge regarding the
repair of 8-oxoG has been derived from studies in Escherichia
coli. 8-oxoG is considered to be a premutagenic lesion because it
can mispair with adenine during DNA replication, and this mispairing
results in G Two groups have independently cloned an
8-oxoguanine glycosylase/AP lyase
from yeast (yOgg1) (21, 22). The enzyme is a functional homolog of the
Fpg protein because the yeast enzyme shares no amino acid homology with
the bacterial protein. The yOgg1 cleaved DNA containing 8-oxoG
opposite pyrimidines, abasic sites (21, 22), and
2,6-diamino-4-hydroxy-5-methylformamidopyrimidine (FapyG) (21).
Cleavage by yOgg1 was consistent with a Recently, the human and the mouse 8-oxoguanine glycosylase/AP lyase
(human OGG1 or mouse Ogg1) genes have been cloned
by their homology to yeast ogg1 (23-25). Human
OGG1 gene was localized to the short arm of chromosome 3, 3p26.2 (23, 25). Expression of the human gene in E. coli
lacking mutM and mutY suppressed the spontaneous
mutator phenotype of these cells (24, 25). Human OGG1 (also called MutM
homolog) was shown to cleave the DNA by a Nash et al. (22) identified another yeast protein, which
preferentially interacted with the substrate 8-oxoG:G; they called the
activity Ogg2. This same substrate preference was observed for the
yeast Fapy DNA glycosylase previously isolated by de Oliveira et
al. (26). Whether these two proteins are the same or not remains
to be determined. In human extracts, an 8-oxoG endonuclease was
identified from human polymorphonuclear neutrophils, which cleaved
8-oxoG but not the ring-opened guanine adduct, FapyG (27). One
distinguishing feature of this enzyme was that it was
magnesium-dependent. Another study identified two repair
activities, an 8-oxoG glycosylase and an 8-oxoG endonuclease, from HeLa
cell nuclear extracts (28). The 8-oxoG base pairing preferences for
these enzymes were similar to that of yeast Ogg1. Further experiments
are required to determine whether these proteins are human OGG1 or
novel enzymes.
In E. coli, the MutY protein is an adenine DNA glycosylase
that removes adenine when base paired with 8-oxoG. Using purified DNA
polymerases, it has been demonstrated that the replicative polymerases
incorporate adenine opposite 8-oxoG (29). A human MutY activity has
been purified from calf thymus cells (30). The protein removes adenine
mispairs including A:G, A/8-oxoG, and A:C. The glycosylase co-purified
with a AP nicking activity, which was inhibited by neutralizing MutY
antibodies. Recently, the gene for a human MutY homolog was cloned
(31).
In cells, the deoxyribonucleotide pools are also subjected to oxidative
damage. dGTP can be converted to 8-oxodGTP and incorporated into
nascent DNA strands opposite adenine. To avoid such damage, cells
possess an 8-oxodGTPase, which hydrolyzes the triphosphate to the
monophosphate so that it can no longer be incorporated into DNA. In
bacteria, the MutT gene product is the 8-oxodGTPase enzyme. A human
MutT homolog has been cloned from a human cell line (32).
Another major adduct generated by oxidative stress is TGs
(cf. Fig. 1). Unlike 8-oxoG, TGs block DNA and RNA
polymerases and are thought to be lethal (33). Endo III is one of the
bacterial enzymes responsible for recognition and removal of TGs;
however, cells lacking endo III are not hypersensitive to
H2O2 or x-rays (34). Subsequently it was shown
that bacteria contain another endonuclease that recognizes TG,
endonuclease VIII (35). In addition, the Uvr ABC complex was shown to
recognize TGs in vitro (36). Recently, a yeast homolog of
endo III has been cloned, NTG1 (endonuclease
three-like glycosylase 1) (37). NTG1 has a
unique substrate specificity; not only does it remove oxidized purines,
but it also recognizes and incises the ring-opened guanine adduct, FapyG. However, it does not incise the 8-oxodG adduct (37).
Deletion of yeast NTG1 renders the cells sensitive to H2O2 and menadione (37).
A mammalian TG glycosylase activity has been purified from extracts of
calf thymus and bovine cells (38). More recently another gene for the
human endonuclease III homolog was cloned (39). Like the bacterial
enzyme endo III, the human enzyme acts on urea and TG residues. It also
contains an iron/sulfur cluster and a helix-hairpin-helix motif.
Apurinic or
apyrimidinic sites (AP sites) are collectively called abasic
sites. These are generated as a consequence of normal spontaneous
hydrolysis of the N-glycosylic bond, by the action of DNA
glycosylases or by oxidative damage to the sugar residues in DNA. AP
endonucleases are enzymes that function to generate suitable DNA ends
for DNA resynthesis or ligation (for reviews see Refs. 40-42). One
major AP endonuclease has been purified from human cells called HAP1
(also called APE, APEX, and Ref-1) (reviewed in Ref. 42). The enzyme
cleaves 5 AP endonucleases are the major pathway whereby AP sites in DNA are
repaired; however, nucleotide excision may also participate (42). In
E. coli, oxidized abasic sites are poorly recognized by
various repair endonucleases (45). It would be interesting to know
whether the mammalian HAP1 also displays this reduced recognition and
incision of oxidized AP sites. If so, then what other pathways
participate in the repair of oxidized AP sites? Do NER proteins
recognize and repair oxidized AP sites?
It is already apparent that repair of oxidative damage by a BER
mechanism in mammalian cells is more complex than in bacteria. Due to
the high levels of endogenous oxidative damage, mammalian cells may
have had to evolve multiple repair mechanisms to survive the daily
insults. Therefore, it may be difficult to define what significance a
particular protein has on the repair of specific types of DNA damage,
and generation of single-gene knock-out mice may not be
informative. Multiple single-gene knock-out mice may have to be
crossbred before a phenotype is observed.
Nucleotide Excision Repair of Oxidative Damage In bacteria and mammalian cells, the repair of oxidative damage is
mediated by both BER and NER mechanisms (46, 47). NER employs a complex
set of proteins that remove damage from DNA (recently reviewed in Refs.
48 and 49). There are two components of NER, a global repair element
and a TCR mechanism. Transcriptionally active genes are repaired at a
faster rate than genes in non-transcriptionally active domains of the
genome and with a strand bias favoring the transcribed DNA strand (50).
The coupling between DNA repair and transcription is mediated via the
basal transcription factor, TFIIH, which contains at least two DNA
repair genes (50). Three genetic disorders have been identified that
have defective NER, xeroderma pigmentosum (XP), Cockayne's syndrome
(CS), and trichothiodystrophy.
Patients with XP are characterized by their acute sun sensitivity and
the development of carcinomas at an early age. Seven complementation
groups of XP have been identified, and several XP and XP/CS groups
develop neurological abnormalities. Studies were performed to determine
whether the oxidative damage repair capacity of the XP cells correlated
with their neurological phenotypes (51, 52). A host cell reactivation
assay was used to measure the capability of two XP-A cell lines to
repair viral DNA, which had been damaged by singlet oxygen (52). The
XP-A cells showed no difference from normal cells. In another study, a
chloramphenicol acetyltransferase reactivation assay was employed to
evaluate the survival of a methylene blue plus light-treated DNA in
XP-A, XP-C, XP-D, and XP-E cell lines. Using seven normal cell lines, the investigators first defined a normal response range and then determined whether the XP cell lines fell within this normal range. Of
the cell lines tested, only the XP-C (3 out of 4) cell lines showed
reduced chloramphenicol acetyltransferase reactivation. Whereas UV
repair is compromised in all XP complementation groups to varying
degrees, the repair of singlet oxygen damage is not. XP-A cells show
the greatest sensitivity to UV damage, and most patients with XP-A have
demonstrable neurological abnormalities. However, XP-A cells appear to
be normal in their repair of singlet oxygen-mediated damage. This
suggests that there is no direct relationship between the accumulation
of singlet oxygen damage in DNA and the development of neurological
defects.
It is possible that an oxidative DNA lesion other than those generated
by singlet oxygen may be critical in the development of neurological
defects in XP cells. This is supported by a study which investigated
whether repair of lesions other than the major oxidative adducts was
defective in NER-deficient XP cell lines. Satoh et al. (46)
treated DNA plasmids with either CS patients are characterized by dwarfism, premature aging, sensitivity
to sunlight, and mental retardation (53). Patients with features of
both XP and CS patients have been identified for XP groups, XP-B, XP-D,
and XP-G (53). CS cells are deficient in the preferential repair of
active genes and TCR of UV-induced pyrimidine dimers (54, 55). There
are two complementation groups of CS, CS-A and CS-B. The genes
CSA and CSB are cloned, but how these genes
facilitate TCR is still not understood (for a recent review see Ref.
53). Recently, the CSB protein has been found to play a direct role in
transcription, both in vitro (56) and in vivo
(57).
CSA, CSB, and XP-A cells were tested for their sensitivity to ionizing
radiation and for their ability to perform TCR after such damage (58).
Both CS-A and CS-B cells showed radiosensitivity to Whereas we have learned much about the heterogeneity, fine structure,
and transcription coupling of repair after UV repair, there is very
little information about such events after oxidative damage. The repair
of UV-induced pyrimidine dimers is known to begin at the nuclear matrix
(60), and it would be interesting to understand the nuclear
organization of the repair of oxidative DNA damage. It may be useful to
focus on individual lesions rather than on the assessment of total
damage since different lesions are repaired via different pathways
(61).
DNA Damage Processing in Mitochondrial DNA Because most ROS are generated by the oxidative phosphorylation
processes that occur in mitochondria, it is of great interest to
understand the oxidative DNA damage-processing mechanisms in these
organelles. It has been observed that mtDNA contains a higher steady-state amount of oxidative DNA damage than nuclear DNA (62). Because mtDNA is subjected to relatively high amount of oxidative damage, it seems that mitochondria would need efficient DNA repair mechanisms to remove oxidative damage from its DNA.
One of the controversies in the study of oxidative DNA damage concerns
the amount of 8-oxodG present in mtDNA. Although there appears to be a
consensus about an increase of damage with age, the amounts of
oxidative base modifications measured by various methods (liquid
chromatography/mass spectroscopy, high pressure liquid chromatography,
and enzymatic) do not agree with one another (13). There is a need to
make concerted efforts to measure oxidative lesions and their repair
under identical conditions using different methods to assess the
same changes. There have been reports of 10-fold higher steady-state
levels of 8-oxodG in mtDNA than in nuclear DNA (62). This finding has
become one of the cornerstones of the mitochondrial theory of aging,
but other observations suggest that it may not be true for cells in
culture (63). There are many possibilities for artefactual formation of
8-oxodG in mtDNA during the purification (13), and this needs thorough
investigation. Comparative studies would determine if variation were
dependent on the type of method used.
The early finding of the absence of repair of UV-induced pyrimidine
dimers in mtDNA led to the general notion that there was no DNA repair
mechanisms in mitochondria (64). Although it has been confirmed that
UV-induced pyrimidine dimers are not repaired in mitochondria, recent
studies clearly show that mitochondria repair their DNA.
Several observations support that mitochondria are capable of oxidative
DNA damage repair. The GSR assay (65) has been modified to detect
repair of oxidative lesions (66). With this approach, it is not
necessary to isolate mtDNA. Bacterial repair enzymes that recognize and
cleave the DNA at specific lesions are used. Oxidative lesions can be
detected in the entire mitochondrial genome or in parts of it and be
compared with the lesions present in the nuclear DNA from the same
biological sample. Also strand bias, or TCR, can be assayed with this
approach.
Using the GSR assay and a variety of damaging agents, repair of strand
breaks and alkali-sensitive sites has been demonstrated in rodent and
human mitochondrial DNA (66, 67). In the latter report (66), the
investigators used alkali in combination with either endo III or Fpg,
and the initial damage frequencies for alkali plus enzyme were not
significantly different than alkali alone, suggesting that they were
primarily measuring repair of AP sites or strand breaks. From these
studies it is apparent that AP sites are efficiently repaired from
mtDNA. Consistent with this observation is the fact that an AP
endonuclease has been partially purified from mitochondria (68).
Oxidative damage, as detected by the Fpg protein, is repaired in mtDNA
from rat cells (16) and Chinese hamster ovary cells (17). In the study
by Taffe et al. (17), acridine orange plus light was used as
a method to generate oxidative damage, and Fpg protein was used in the
GSR assay to assess repair of Fpg-sensitive sites. The acridine orange
plus light-induced DNA damage was repaired from both mitochondrial and
nuclear DNA sequences. Approximately 65% of the lesions were repaired
within 4 h, and the repair in the mtDNA was as fast or faster than
in the nuclear dihydrofolate reductase gene. The efficient repair of
the Fpg-sensitive sites suggested that mitochondria contain a base
excision repair protein, such as a Fpg homolog. Recently, in this
laboratory, an 8-oxodG incising activity has been partially purified
and characterized from rat liver mitochondria
(69).
A polymerase extension assay has been utilized to evaluate
H2O2 damage induction and removal (70). Both
nuclear and mitochondrial sequences were evaluated. This assay is not
measuring a specific lesion but rather any damage that blocks the
progression of the polymerase. Repair of
H2O2-mediated damage in mitochondria was as
efficient as in nuclear DNA when a brief H2O2
exposure was used, whereas at higher levels of exposure mitochondrial
DNA repair was not observed within 3.5 h of post-treatment.
Whereas in vitro DNA repair assays have proven very useful
in the exploration of the NER mechanisms, no such assays have been available for the mitochondrial DNA until very recently. In one study,
the DNA repair incorporation assay was used to demonstrate that plasmid
DNA treated with hydrogen peroxide was repaired using Xenopus mitochondria protein extracts (71). More in
vitro studies are needed.
Interestingly, complex lesions such as cisplatin interstrand
cross-links, which are thought to be repaired via a recombination repair pathway, are removed from hamster mtDNA (72). This would suggest
that mitochondria possess recombinational activities. Recently there
has been support for this hypothesis; an in vitro assay has
demonstrated recombination between plasmids using human mitochondrial
protein extracts (73). Another complex lesion that is removed from
mitochondrial DNA is 4-nitroquinoline DNA damage (74). 4-Nitroquinoline
damage is generally thought to be removed via a NER pathway. However,
NER as it exists in the nucleus does not exist in mitochondria. Whether
any NER proteins participate in mitochondrial repair remains to be
explored.
In addition to DNA repair mechanisms, mitochondria also contain an
error avoidance mutT homolog. The replicative polymerase in
mitochondria, polymerase By several different methods, it is apparent that mitochondria possess
the ability to remove oxidative DNA damage. Whether mitochondria
utilize the same proteins as the nucleus or different ones will await
their biochemical purification and cloning.
Conclusions and Perspective DNA accumulates oxidative damage as a consequence of its inherent
instability and constant insult by reactive oxygen species generated by
endogenous and exogenous sources. The maintenance of the DNA genomes,
both nuclear and mitochondrial, is dependent upon proficient repair
mechanisms that remove oxidative damage. The repair of oxidative damage
is well defined in bacteria, whereas in higher eukaryotes the genes and
proteins responsible for repair have not been extensively
characterized.
Contrary to the existing notion, mitochondria possess DNA repair
mechanisms. Indeed, some oxidative damage, such as strand breaks and
8-oxoG, is repaired in mtDNA. Exploration of mitochondrial DNA damage
processing is going to be an important area of research in the next
years.
New insight into the repair mechanisms of oxidative DNA damage is
emerging very quickly. It clearly involves a contribution of both BER
and NER and other pathways. There may be well over 100 types of
oxidative base modifications in mammalian DNA, and the accumulation of
a single type or of multiple types of oxidative lesions may have
deleterious consequences for the cells, such as disease or neurological
deficits.
FOOTNOTES ACKNOWLEDGEMENTS We thank M. Anson and Drs. L. Lipinski, R. Stierum, and R. Brosh for comments.
REFERENCES
Volume 272, Number 41,
Issue of October 10, 1997
pp. 25409-25412
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
MINIREVIEW:
INTRODUCTION
Oxidative DNA Damage and Its Consequences
Base Excision Repair of Oxidative Damage
Nucleotide Excision Repair of Oxidative Damage
DNA Damage Processing in Mitochondrial DNA
Conclusions and Perspective
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
Fig. 1.
Examples of oxidative base
modifications found in mammalian DNA.
[View Larger Version of this Image (17K GIF file)]
-deoxyribose moiety and generate a 3-hydroxyl group, which can
be extended by a DNA polymerase. The process is completed by a DNA
ligase rejoining the free DNA ends (for reviews see Refs. 18 and
19).
T transversion mutations (20). Bacteria possess an
integrated system of BER and error avoidance mechanisms to prevent
damage at guanines (for a review see Ref. 20). This system is comprised of three components, an 8-oxoG glycosylase/AP lyase enzyme, called MutM or Fpg protein, an adenine DNA glycosylase, MutY, and a
8-oxodGTPase, MutT. As will be discussed, functional homologs of each
of these proteins have now been identified in higher eukaryotes.
-elimination mechanism (21,
22).
-elimination mechanism
preferentially at 8-oxoG:C base pairs (23, 24). Several conserved
domains have been identified in the yeast, mouse, and human genes
including the a helix-hairpin-helix (HhH) and Gly/Pro-rich-Asp motif
(GPD motif) (22, 23, 25). In addition, Arai et al. (25)
reported that the yeast Ogg1 and human OGG1
contained a putative C2H2 zinc finger-like
motif, although in the yeast sequence one of the histidines was an
arginine. Alignment of the ogg1 genes with other DNA repair
glycosylases suggests that these enzymes may represent a DNA repair
superfamily (18, 22, 23, 25).
to the AP site leaving a 5-deoxyribose moiety and a
3-hydroxyl group on the DNA ends. In addition to the AP endonuclease
activity, the enzyme possesses several other activities including a
3-phosphatase, 3-phosphodiesterase, and a very weak exonuclease
activity (42-44).
-irradiation or hydrogen peroxide
plus copper and then removed the major adducts by treating the plasmids
with the Fpg protein and endo III (46). They then assayed whether XP-A,
XP-B, XP-C, XP-D, and XP-G cell extracts were able to perform DNA
repair synthesis on such substrates. All XP cell lines showed reduced
DNA repair synthesis as compared with normal cell extracts. The
specific lesion in the plasmid DNA, which was dependent on NER for
repair, was proposed to be purine dimers. The authors concluded that
although repair of the major oxidative lesions is not impaired in XP
cell extracts, there could be some endogenous oxidative lesions that
are formed at low levels, require NER for repair, that accumulate in XP
patients, and lead to neurological defects.
-rays whereas
XP-A and normal cells did not. Using an antibody that recognizes repair
patches, gene-specific repair was measured, and it was observed that
CS-A and CS-B cells were defective in preferential repair of 10 gray of
-rays. Normal and XP-A cells showed normal TCR of -rays. In a
subsequent paper, TGs were shown to be repaired by a
transcription-coupled repair mechanism, and this repair was defective
in CS-B and XP-G/CS cells (59). The TCR of thymine glycols in
XP-A, XP-F, and XP-G cells was shown to be normal, demonstrating that
TCR of this oxidative lesion can continue in the absence of NER. Thus,
there appears to be a NER-independent transcription-coupled repair
pathway that utilizes CS-A, CS-B, and XP-G. The exact roles of the CS
and XP-G proteins are under investigation in a number of
laboratories.
, readily misincorporates 8-oxoG opposite
adenine (75). To avoid such damage mammalian mitochondria have their
own mutT homolog, which hydrolyzes 8-oxodGTP to
8-oxodGMP (76).
1
The abbreviations used are: ROS, reactive oxygen
species; BER, base excision repair; NER, nucleotide excision repair;
AD, Alzheimer's disease; endo, endonuclease; TCR,
transcription-coupled repair; 8-oxoG, 8-hydroxyguanine; 8-oxodG,
8-hydroxydeoxyguanine; TG, thymine glycol; AP, apurinic/apyrimidinc;
GSR, gene-specific repair assay; XP, xeroderma pigmentosum; CS,
Cockayne's syndrome; FapyG,
2,6-diamino-4hydroxyl-5-methylformamidopyrimidine.
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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C. Cao, Y. Leng, and D. Kufe Catalase Activity Is Regulated by c-Abl and Arg in the Oxidative Stress Response J. Biol. Chem., August 8, 2003; 278(32): 29667 - 29675. [Abstract] [Full Text] [PDF]
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 N. R. Bianco, G. Perry, M. A. Smith, D. J. Templeton, and M. M. Montano Functional Implications of Antiestrogen Induction of Quinone Reductase: Inhibition of Estrogen-Induced Deoxyribonucleic Acid Damage Mol. Endocrinol., July 1, 2003; 17(7): 1344 - 1355. [Abstract] [Full Text] [PDF]
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C. Cao, Y. Leng, C. Li, and D. Kufe Functional Interaction between the c-Abl and Arg Protein-tyrosine Kinases in the Oxidative Stress Response J. Biol. Chem., April 4, 2003; 278(15): 12961 - 12967. [Abstract] [Full Text] [PDF]
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 E. Mambo, X. Gao, Y. Cohen, Z. Guo, P. Talalay, and D. Sidransky Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations PNAS, February 18, 2003; 100(4): 1838 - 1843. [Abstract] [Full Text] [PDF]
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