Download Genetic alterations and DNA repair in human carcinogenesis

Seminars in Cancer Biology 14 (2004) 441–448
Genetic alterations and DNA repair in human carcinogenesis
Kathleen Dixon∗ , Elizabeth Kopras
Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Abstract
A causal association between genetic alterations and cancer is supported by extensive experimental and epidemiological data. Mutational
inactivation of tumor suppressor genes and activation of oncogenes are associated with the development of a wide range of cancers. The
link between mutagenesis and carcinogenesis is particularly evident for cancers induced by chemical exposures, which, in some cases,
lead to characteristic patterns of mutations. These “genotoxic,” direct-acting carcinogens form covalent adducts with DNA, which cause
mutations during DNA replication. The link between mutagenesis and carcinogenesis is also supported by the observation that DNA repair
defects are associated with an increased cancer risk. Normally, DNA repair mechanisms serve to suppress mutagenesis by correcting DNA
damage before it can lead to heritable mutations. It has been postulated that mutagenesis plays a role in both the initiation phase and the
progression phase of carcinogenesis, and that an essential step in the carcinogenic process is the development of a mutator state in which
the normal cellular processes that suppress mutagenesis become compromised. Given the link between mutations and cancer, attempts
have been made to use the mutational profile of cancer cells as an indicator of the causative agent. While this may be a valid approach in
some cases, it is complicated by the role of endogenous processes in promoting mutagenesis. In addition, many important carcinogenic
agents may enhance mutagenesis indirectly through suppression of DNA repair functions or stimulation of inappropriate cell proliferation.
Epigenetic phenomena may also suppress gene expression without causing overt changes in DNA sequence.
© 2004 Elsevier Ltd. All rights reserved.
Keywords: DNA repair; Mutagenesis; Tumor suppressors; Oncogenes
1. Genetic alterations in cancer
The association between genetic alterations and human
cancer was first observed decades ago [1]. Cytogenetic studies revealed that specific chromosomal abnormalities were
linked to the development of certain cancers. For example, a chromosomal translocation (the Philadelphia chromosome) was frequently found in white blood cells of leukemia
patients. In addition, tumor cells often exhibited extensive
genetic instability leading to chromosome aberrations, rearrangements, and aneuploidy. However, it was not clear
whether this widespread genetic instability was a cause or
a consequence of the cancer phenotype. An understanding of the role of genetic alterations in cancer development
arose out of studies of oncogenic viruses and hereditary
cancers. RNA tumor viruses were found to express certain
“oncogenes” (e.g., c-ras and c-myc) that contributed to the
transforming activity of the viruses and that had homologous
counterparts (proto-oncogenes) in the human genome. Later,
it was shown that RAS and MYC were over-expressed in
cancer cells, often due to genetic translocations that placed
∗ Corresponding
author. Tel.: +1 513 558 1728; fax: +1 513 558 3509.
E-mail address: [email protected] (K. Dixon).
1044-579X/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.semcancer.2004.06.007
the genes under the control of strong heterologous promotors. The study of human retinoblastoma led to the discovery of the RB tumor suppressor gene; loss of function of
this gene through inheritance of one mutant allele and the
somatic loss of the other allele lead to the formation of retinal tumors in children. Another important tumor suppressor
protein, p53, was first identified as a target for the SV40 tumor virus, and was later found to be inactivated in a variety
of tumor cells, and also in Li-Fraumeni syndrome, which is
associated with a high cancer risk. Both point mutations and
deletions are found among inherited and somatic mutations
that inactivate RB and TP53; in addition, loss of the second
allele in the inherited cancers can often occur though loss
of part or all of one of two homologous chromosomes.
A large number of tumor suppressor genes and oncogenes
have now been identified and characterized through the analysis of tumor cell DNA [1–4]. It has been postulated that the
minimum constellation of mutations required for oncogenic
transformation in humans includes inactivation of TP53 and
RB, activation of RAS (or other members of that pathway),
and constitutive expression of hTERT [5–7]. These genes
control cellular functions that prevent uncontrolled proliferation (Fig. 1). The most prevalent mutations in human
cancers occur in the tumor suppressor genes, TP53 and RB
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K. Dixon, E. Kopras / Seminars in Cancer Biology 14 (2004) 441–448
Fig. 1. Genetic alterations in cancer. Cancer develops over time as a
consequence of successive mutation and expansion of mutant clones. Mutations that inactivate tumor suppressor genes, activate proto-oncogenes,
and turn on telomerase stimulate cell proliferation and inhibit cell death,
providing a growth advantage.
[5]. Both base substitution mutations and gene deletions in
these genes are found in a wide variety of cancer types [8].
The Rb protein is a key regulator of the cell cycle, and loss
of this function can lead to increased cell proliferation and
a failure in terminal differentiation, i.e., an increase in the
“birth rate” of cells [7]. The p53 protein is important in cellular responses to stress, controlling DNA repair, cell cycle
checkpoints, and apoptosis [9]. Perhaps, the most important
of these pathways for cancer development is apoptosis; loss
of p53 function can lead to decreased apoptosis, i.e., a decrease in the “death rate” of cells. Thus, loss of these two tumor suppressor genes leads to a net increase in cell numbers
due to an increased birth rate and a decreased death rate.
Cancer development can also be promoted through mutations that activate the expression of proto-oncogenes that
regulate cell proliferation [5]. These are genes for secreted
growth factors (e.g., PDGF), cell surface tyrosine kinase receptors (e.g., EGFR, HER), signal transduction G-proteins
(e.g., RAS), and nuclear transcription factors (e.g., MYC)
[10]. RAS mutations are found in about 20% of tumors, including colon, lung, breast, and bladder cancer. Activating
mutations are often missense mutations that decrease the
GTPase activity of the protein and prolong RAS-dependent
signaling. The MYC gene is often activated by DNA rearrangements that place the proto-oncogene under the control
of a strong promoter, or gene amplification events that increase expression through an increase in gene copy number.
The net effect of activation of these proto-oncogenes is the
stimulation of cell proliferation, leading to the expansion of
the transformed cell population and augmenting the effects
of loss of tumor suppressor function. A related set of genes
that operate in signal transduction are responsible for certain inherited conditions characterized by the development
of scattered benign lesions that occasionally become malignant [3]. For example, the neurofibromatosis (NF1) gene
product regulates the RAS pathway, and the familial adenomatous polyposis (APC) gene regulates the WNT pathway. Affected individuals inherit mutations on one allele,
and mutation of the second allele appears to be necessary
for development of the benign lesions; further progression
requires additional genetic “hits”.
An additional requirement for cancer development is cell
“immortalization.” Normal cells are able to undergo only
a finite number of cell divisions before they reach “crisis”
and die. This phenomenon has recently been attributed to a
gradual shortening of the small repeat telomere sequences
at the ends of chromosomes that protect them from both
degradation and end-to-end fusions. The absence of telomeres leads to genetic instability and ultimately apoptotic cell
death. Tumor cells overcome this process by switching on
the gene (hTERT) telomerase, an enzyme that maintains
telomere length [6].
2. Mutation spectra
Extensive analysis of mutations in the TP53 gene has
revealed that inactivating mutations are widely distributed
throughout the gene, but certain types of mutations are more
prevalent in some cancers than in others [8]. For example,
in the case of sunlight-induced carcinoma, tandem double
mutations at adjacent pyrimidines are observed at high frequency [11,12]; such mutations are rarely observed in other
cancers. This observation is consistent with the fact that the
UV portion of the sun’s spectrum dimerizes adjacent pyrimidines in skin, and such lesions have been shown to preferentially lead to tandem double mutations in in vitro mutagenesis assay systems [13,14]. Another example is the analysis of TP53 mutations in primary liver cancer derived from
patients exposed to aflatoxins, carcinogenic metabolites of
certain spoilage molds [15]. In this case, a high frequency of
G:C-to-T:A mutations at the third base in codon 249 were
observed. A similar pattern of aflatoxin-induced mutations
was observed in mutagenesis test systems [16], and this correlation was used to strengthen the causal link between exposure to aflatoxins and liver carcinogenesis in epidemiological studies [15]. An extensive database of tumor-associated
TP53 mutations has been compiled (www.iarc.fr/p53) [17]
and certain additional associations between environmental
K. Dixon, E. Kopras / Seminars in Cancer Biology 14 (2004) 441–448
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Fig. 2. TP53 mutations in lung cancer. Diagram from the IARC TP53 mutation database (R8, June 2003) [17]. Analysis of mutations in TP53 from a
variety of lung tumors reveals characteristic hotspots for mutagenesis.
exposures and mutational spectra have emerged. An example of one such association is shown in Fig. 2; there appears to be an association between G:C-to-T:A mutations
at codons 157, 158, 245, 248, 249, and 273 in TP53 and
cigarette smoking-associated lung cancer [18]. While these
associations cannot confirm the link between a particular exposure and cancer development in a single individual, they
are suggestive of a link on a population basis.
In an attempt to determine whether general rules for the
mutagenic specificity of carcinogens could be derived from
the analysis of mutational patterns (mutation spectra) of individual carcinogens, several different mutation assay systems have been used [19]. One such system, the pZ189
shuttle vector system, has been used to analyze the specificity of almost 40 different carcinogens [20]. Cluster analysis of these mutation spectra revealed patterns of mutational
specificity that roughly corresponded to the known chemical specificity of the agents. For example, chemicals that are
known to form DNA adducts preferentially on G residues
formed mutations preferentially at G:C base pairs, and those
known to form DNA adducts preferentially on A residues
formed mutations preferentially at A:T base pairs. In cases
where whole classes of mutagenic agents form similar mutation spectra, back extrapolation from the characteristics of
mutations in tumors to the identity of the causative agent is
not possible. However, in cases where the mutational pattern is more unique (e.g., UV and aflatoxins), such back extrapolation can provide support with regard to questions of
cancer causation.
Additional mutation analysis systems have been established that allow determination of mutational specificity in
experimental animals [21]. In some of these systems, it is
possible to examine target organ specificity as well as muta-
tional patterns. Of these, the most widely used mutagenesis
reporter genes are the endogenous APRT [22,23] and HPRT
[24] genes, and the Escherichia coli lacI or bacteriophage
lambda cII transgenes [25]. The X-chromosomal HPRT gene
has been used as a mutagenesis target for somatic mutations
in peripheral blood lymphocytes of both humans and animals. Not only is this a useful reporter gene for point mutations, but it also reveals the activation of pathways normally
involved in gene rearrangements that can trigger the generation of deletion mutations. The heterozygous APRT± mouse
has been particularly useful for understanding events that
lead to loss of heterozygosity (LOH), a common mechanism
for loss of the second allele in many inherited cancers. The
Big BlueTM mouse system [25] carries an integrated bacteriophage lambda-based vector, ␭LIZ, which contains the
E. coli lacI and lacZα genes; either the lacI or the lambda
cII genes can be assayed for mutations in DNA recovered
from mouse tissues. This system has been used widely for
tissue-specific analysis of mutagenesis [26]. Although each
of these systems has unique properties, generally they reveal
similar patterns of mutational specificity of environmental
carcinogens.
3. Mutation avoidance: DNA repair and
checkpoint pathways
Cells have elaborate mechanisms for safeguarding the informational integrity of the genome and suppressing mutations. Mutation avoidance mechanisms include: (1) multiple
checks and balances within the DNA replication complex
that insure high fidelity DNA replication (<1 error in 106
nucleotides incorporated [27]); (2) pathways that suppress
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K. Dixon, E. Kopras / Seminars in Cancer Biology 14 (2004) 441–448
Fig. 3. DNA damage responses. Cells respond to DNA damage by activating a variety of DNA damage response pathways. If the DNA damage
is excessive, cells die through induction of apoptosis. Alternatively, cell
cycle checkpoints are induced that delay cell cycle progression to allow
time for DNA repair to occur. Specific DNA repair pathways recognize
and repair specific types of DNA damage. In the absence of DNA repair,
the DNA damage results in mutations.
oxidative stress, which can result from endogenous
metabolic processes and lead to oxidative DNA damage
[28]; (3) pathways that regulate cell cycle progression to insure an orderly duplication and segregation of chromosomes
[29]; and (4) DNA repair pathways that correct all types of
DNA damage caused by endogenous processes or exogenous agents (Fig. 3) [30–32]. More than 130 genes have
been identified that contribute to DNA repair. The importance of these mechanisms in cancer prevention is evident
from the increased cancer risk associated with disruption of
these pathways (Table 1) [33]. This is particularly evident
from the study of a wide variety of familial cancers. One of
the first widely studied hereditary diseases associated with
increased cancer risk was xeroderma pigmentosum [34,35].
This defect in nucleotide excision repair leads to a dramatic
increase in the risk of sunlight-induced skin cancer. Individuals with this condition are unable to excise and repair
UV photoproducts in skin DNA, so that mutagenesis and
carcinogenesis are increased.
Nucleotide excision repair is important for the removal of
a wide variety of premutagenic DNA lesions in addition to
UV photoproducts, including most bulky DNA adducts. In
humans, the process of nucleotide excision repair requires
more than 30 proteins [35]. These proteins are involved in
DNA damage recognition, single-strand incision on either
side of the lesion, excision of the single-stranded region
containing the lesion, DNA repair synthesis, and ligation.
XPA–XPG are required for “global genome repair” (GGR),
which serves to repair lesions throughout the genome.
“Transcription-coupled repair” (TCR), which occurs mainly
in transcribed regions of the genome, requires the Cockayne syndrome gene products (CS-A and CS-B), as well as
the XP proteins, and is important in cell survival. Increased
cancer risk is associated primarily with defects in the XP
genes and not the CS genes.
The high fidelity of DNA replication is normally maintained by the accuracy of DNA polymerase ␦; compromising
the DNA polymerase ␦ proofreading function can cause an
increase in mutation rate, and can lead to an increased cancer risk in transgenic mice [36]. Furthermore, an increase
in the expression of the less accurate DNA polymerase ␤,
which normally functions in DNA repair, can also increase
mutagenesis and is associated with cancer [37]. Certain less
Table 1
Hereditary cancer syndromes with defects in DNA repair and checkpoint pathways
Pathway
Genes
Syndrome
Cancer type
Mismatch repair
MSH1, MSH2, MLH1,
MSH6, PMS1, PMS2,
XPA–XPG
XPV
NBS1
HNPCC
Colon cancer
Xeroderma pigmentosum (XP)
XP variant
Nijmegen breakage syndrome
Skin cancer
Skin cancer
Lymphoma
MRE11
WRN
BLM/RECQL3
BRCA1, BRCA2
FANCA-FANCG
ATM
A-T-like disorder
Werners syndrome
Blooms syndrome
Familial breast cancer
Fanconi anemia
Ataxia telangiectasia (A–T)
Lymphoma/leukemia
Various
Leukemia, carcinomas
Breast/ovarian cancer
Leukemia
Lymphoma/leukemia
TP53
RB1
Li-Fraumeni syndrome
Retinoblastoma
Various
Retinoblastoma
Nucleotide excision repair
Replication bypass
Replication fork integrity;
double-strand break repair
DNA crosslink repair
DNA damage signaling; cell
cycle checkpoints
K. Dixon, E. Kopras / Seminars in Cancer Biology 14 (2004) 441–448
accurate “bypass” polymerases can also cause mutations that
contribute to carcinogenesis. In the cancer-prone human genetic disorder, xeroderma pigmentosum variant (XP-V), the
function of DNA polymerase η, which can accurately bypass UV-induced TT dimers, is replaced by less accurate
DNA polymerases, leading to higher UV-induced mutation
rates and a higher risk of sunlight-induced cancer [38,39].
The importance of the mismatch repair pathway in the prevention of mutagenesis and carcinogenesis is illustrated by
the large increase in cancer risk in individuals with mismatch
repair defects. Defects in mismatch repair genes are associated with increased cancer risk in hereditary non-polyposis
colon cancer (HNPCC) [40]. The mismatch repair system is
responsible for removal of base mismatches caused by base
deamination, oxidation, methylation, and DNA replication
errors. The mismatch is recognized, and one of the two DNA
strands is selectively excised, which is followed by repair
synthesis and ligation of the resulting single-stranded DNA
gap. Mutation of mismatch repair genes is associated with
microsatellite instability and an increased rate of somatic
mutations.
A number of genes associated with increased cancer risk
are important for DNA damage signaling, cell cycle checkpoints, and DNA double-strand break (DSB) repair (Table 1)
[30]. The conversion of premutagenic DNA lesions (e.g., UV
photoproducts, DNA adducts, etc.) to heritable mutations
often requires active DNA replication and/or mitosis. Replication of damaged templates can result in replication errors
or replication fork blockage. When progression of replication forks is blocked by DNA damage, a number of recovery mechanisms are induced, some of which are thought to
involve RecQ-like helicases, such as BLM [41] and WRN
[42]. Blocked replication forks can also result in the induction of DSBs, and the MRN complex (MRE11, RAD50, and
NBS) participates in their repair [43]. BRCA1 and BRCA2
are also thought to participate in DSB repair [44]. The FANC
genes appear to be required for repair of DNA crosslinks
[45]. Human cells have multiple regulatory pathways (called
cell cycle checkpoints) that are activated by DNA damage
and that arrest cell cycle progression to allow time for DNA
repair to occur [46]. For example, the protein kinase encoded
by the ATM gene, which is mutated in the human genetic
disorder ataxia telangiectasia (A–T), has an important regulatory role in DNA damage response [47]. This kinase is
activated in response to many types of DNA damage, and it
in turn activates other proteins responsible for cell cycle regulation and DNA repair. Individuals with A–T are sensitive
to certain DNA-damaging agents and exhibit a dramatically
increased cancer risk. The ATM kinase phosphorylates a
number of proteins required for cell cycle checkpoints (e.g.,
p53) and DSB repair (e.g., NBS1). Loss of these functions
results in genomic instability and increased cancer risk.
Given the importance of DNA repair pathways in cancer
prevention, it is reasonable to speculate that disruption of
these pathways by exogenous agents could contribute to carcinogenesis as well. Such an agent would be expected to act
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as a co-carcinogen, and enhance the mutagenic and carcinogenic activity of genotoxic carcinogens. A possible example
of this type of co-carcinogen is arsenic [48]. Epidemiological studies show that arsenic exposure is strongly associated
with the development of skin lesions, including skin cancers
[49,50]. Elevated risk of other malignancies, such as bladder, lung, kidney, and liver carcinomas, is also associated
with arsenic exposure. Tests of the mutagenic activity of arsenic in a variety of assay systems have generally been negative (with a few exceptions) [51]. However, in cell culture
systems, arsenic has been shown to enhance the mutagenic
activity of other carcinogenic agents. This enhancement of
mutagenesis was shown to be associated with a suppression
of DNA repair [48]. Recently, arsenic was shown to act as
a co-carcinogen with UV radiation in the induction of skin
tumors in the hairless mouse [52]. These results suggest that
the carcinogenic activity of arsenic may be due in part to
its ability to suppress DNA repair pathways. Certainly, it is
possible that other environmental agents may increase cancer risk by similar mechanisms.
4. Mutators, cell proliferation, and cancer
development – how many mutations?
Most solid tumors that have been studied cytogenetically
appear to be genetically unstable; aneuploidy and chromosomal rearrangements are common features of tumor cells.
It has been estimated that some tumor cells may have thousands of mutations. However, it is not clear whether genetic instability is a prerequisite for cancer development or
whether it is a consequence of the cancer phenotype. Certainly, as discussed above, defects in cell cycle checkpoints
and DNA repair pathways that increase genetic instability
also increase cancer risk. Is induction of such a “mutator”
phenotype an essential step in the carcinogenic process? The
arguments on both sides of this question [53] depend on assumptions concerning the number of mutations required for
cancer development and the rate of cell division. The argument in favor of this hypothesis [54] assumes that at least
five “hits” (mutations) are required for cancer development.
Given a normal somatic mutation rate of about 10−6 per cell
doubling, the probability of the five independent hits occurring in a single cell is 10−30 per cell doubling. Even considering that there are perhaps 1014 cells in the body and
perhaps 50 cell divisions during the average life span, this
leads to a calculated cancer risk of 10−15 . Since cancer is
much more prevalent than that, this suggests that an essential step in cancer development is an increase in mutation
frequency. This increase could be due to an inhibition of any
of the pathways that normally serve to maintain genomic
stability. Whether disruption of normal mutation-avoidance
pathways (e.g., DNA repair, DNA damage signaling pathways, etc.) is also responsible for such genomic instability
remains to be demonstrated. Although it is clear that an increase in mutagenesis can promote cancer development, it
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K. Dixon, E. Kopras / Seminars in Cancer Biology 14 (2004) 441–448
has been argued that, at least in some highly proliferative
tissues, induction of a mutator phenotype would not be a
prerequisite for cancer development [3,7]; in these cases,
enough cell divisions could occur within a stem cell population to allow for accumulation of mutations that provide
a selective advantage and clonal expansion [55]. Thus, the
counter argument invokes proliferation and selection of mutant cells. If the first “hit” provides a growth advantage to
the cell, this cell will proliferate, increasing the probability
of a second hit within the expanded population. Either argument is consistent with the observed increase in cancer
incidence with age – a longer time and more cell divisions
increase the probability of generating the mutator state or
allowing for rounds of mutagenesis and clonal expansion.
It has been postulated that stimulation of cell proliferation by tumor promoters, natural hormones, or as a result
of cell injury can enhance the mutagenic effects of endogenous or exogenous genotoxic agents [56,57]. A wide variety of non-mutagenic agents that stimulate cell proliferation can increase cancer risk, perhaps through the enhancement of mutagenesis. The link between cell proliferation
and mutagenesis has been demonstrated in mouse model
systems. For example, a classical tumor promoter, phorbol
12-myristate 13-acetate (TPA), increased the frequency of
benzo[a]pyrene-induced mutations in the non-selected lacI
gene in the Big BlueTM mouse by promoting cell division in
the damaged cell population [58]. Likewise, the mutagenicity of N-ethyl-N-nitrosourea was dramatically enhanced in
the liver by partial hepatectomy, which stimulates cell proliferation [59]. It is possible that cell turnover caused by
chronic infections, proliferation of target tissues induced by
hormones, such as estrogen, or hyperplasia due to exposure
to environmental agents, such as arsenic, may all enhance
mutagenesis. In addition, such agents likely stimulate expansion of mutant cell populations that may have a selective
advantage. Both these effects likely contribute to the link between stimulation of cell proliferation and increased cancer
risk.
times leading to chromosome condensation. There appears
to be a relationship between DNA methylation and histone
modifications; patterns of histone deactylation and histone
methylation are associated with DNA methylation and gene
silencing. Interestingly, these epigenetic changes in chromatin can also alter the sensitivity of DNA sequences to
mutation, thus rendering genes more susceptible to toxic insult. The relationship of chromatic structure to gene expression, DNA repair, and mutagenesis is an important area for
further study in carcinogenesis.
6. Concluding remarks
Given the importance of preserving genomic stability in
cancer prevention and the critical role that DNA damage
signaling and repair pathways play in mutation avoidance, it
may be important to ask whether these pathways may offer
a potential site for intervention in the carcinogenic process.
Many of the damage response pathways have only recently
been identified, and aspects of these pathways remain to be
elucidated. Although it is clear that protein kinases such as
ATM are important in DNA damage sensing and activation
of downstream effectors, it is not well understood how the
various responses (i.e., cell cycle checkpoints, replication
fork maintenance, DNA repair, etc.) are activated, and how
these are coordinated to minimize mutagenesis. Indeed, in
some cases, mutagenesis may be the lesser of the two evils
when the alternative is wholesale cell death brought about
by excessive DNA damage. In any case, it would seem reasonable to postulate that by somehow enhancing the mutation avoidance pathways, it might be possible to mitigate
the carcinogenic effects of environmental agents. Perhaps,
opportunities for intervention will be suggested as further
research reveals the details of these elaborate cellular DNA
damage response pathways.
Acknowledgements
5. Epigenetic mechanisms of gene
activation and silencing
A discussion of genetic alterations in human cancer would
be incomplete without addressing the role of epigenetic phenomena in regulation of gene expression. While activation
of proto-oncogenes and inactivation of tumor suppressor
genes by mutations (base substitutions, deletions, DNA rearrangements, etc.) are certainly well documented, alterations
in expression of cancer genes can also occur by epigenetic
mechanisms [4,60,61] [62]. The most well-understood epigenetic mechanisms involve DNA methylation and histone
acetylation, methylation, and phosphorylation. Demethylation of promoter regions at the CpG sequences can lead to
over-expression of proto-oncogenes, and silencing of gene
expression can occur as a result of hypermethylation, some-
The helpful suggestions of Joseph R. Testa is gratefully acknowledged. This work was supported by grants
R01-NS34782, P42-ES04908, and P30-ES06096 from the
National Institutes of Health.
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