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J Carcinog Mutagen. 2014 ; 5: . doi:10.4172/2157-2518.1000165.

Genomic Instability and Cancer

Yixin Yao1,* and Wei Dai1,2,*
1Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo,
New York, 10987, USA.
2Department of Biochemistry and Molecular Pharmacology, New York University Langone
Medical Center, Tuxedo, New York, 10987, USA.

Abstract
Genomic instability is a characteristic of most cancer cells. It is an increased tendency of genome
alteration during cell division. Cancer frequently results from damage to multiple genes
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controlling cell division and tumor suppressors. It is known that genomic integrity is closely
monitored by several surveillance mechanisms, DNA damage checkpoint, DNA repair machinery
and mitotic checkpoint. A defect in the regulation of any of these mechanisms often results in
genomic instability, which predisposes the cell to malignant transformation. Posttranslational
modifications of the histone tails are closely associated with regulation of the cell cycle as well as
chromatin structure. Nevertheless, DNA methylation status is also related to genomic integrity.
We attempt to summarize recent developments in this field and discuss the debate of driving force
of tumor initiation and progression.

I. INTRODUCTION
The maintenance of genomic stability is essential for cellular integrity to prevent errors from
DNA replication, endogenous genotoxic stress such as reactive oxygen species (ROS) from
cellular metabolism, and exogenous carcinogen insults; for example, ultraviolet light,
ionizing radiation or DNA damaging chemicals. It is believed that tumor initiation and
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progression result from acquired genomic alteration within the original normal cells, and
selection of more aggressive sub clones as an aftermath(Nowell 1976). Tumor cell
population appears to be more genetically unstable than normal cells. The genomic
instability provides individuals a shorter cell cycle and/or an advantage of bypassing
intracellular and immunological control systems, thereby give cancerous cells a growth
advantage and being selected as malignantly transformed cells. Much research has been
directed toward genomic instability to understand and control the initiation and progress of
tumors in hope of conquering cancer, a worldwide leading cause of death.

Genomic instability includes small structure variations such as increased frequencies of base
pair mutation, microsatellite instability (MSI), as well as significant structure variation such

*
To whom corresponding should be addressed: Wei Dai, Ph.D. [email protected] Yixin Yao, M.D. Ph.D. [email protected]
Departments of Environmental Medicine New York University Langone Medical Center 57 Old Forge Road Tuxedo, New York, USA
Tel: 845-731-3555 Fax: 845-731-3611.
 Yao and Dai Page 2

as chromosome number or structure changes, which is also called chromosome instability

(CIN)(Al-Sohaily et al. 2012, Roschke and Kirsch 2010). The mechanisms underlying the
origin of these instabilities still remain elusive, but there are several hypotheses trying to
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explain the driving force of tumor initiation and progression through genomic instability.
The major ones include (1) mutator phenotype results from loss of gene function and (2)
oncogene induced DNA replication stress model (Loeb 1991, 2001, Negrini et al. 2010).
Here in this chapter, we are going to discuss the evidence supporting or disputing these
hypotheses and new research findings in this area.

II. GENOMIC INSTABILITY

A. Increased Frequencies of Base Pair Mutation
Evidence has been found in hereditary cancers that loss of function of DNA repair genes
will cause increased frequencies of base pair mutation. For example, hereditary MYH-
associated polyposis, in which biallelic germline mutations in MYH, a DNA base excision
repair (BER) gene, results in increased G•C to T•A transversion frequencies and cancer (Al-
Tassan et al. 2002).
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This evidence along with MSI found in other hereditary DNA damage repair gene mutation
cases have indicated that loss of genomic integrity maintenance genes might be a cause of
genomic instability as well as the initiation of cancer. It has been proposed that an early step
in tumor progression is the expression of a mutator phenotype resulting from mutations in
genes that normally function in the maintenance of genetic stability (Loeb 2001).

B. MSI
Microsatellites are simple tandem nucleotide repeats, repetitive motifs of 1 to 6 nucleotides,
scattering widespread the human genome (Ellegren 2004). MSI has been detected in many
solid malignancies. It is most commonly found in hereditary malignancies such as the
hereditary nonpolyposis colorectal cancer syndrome (HNPCC) (Aaltonen et al. 1993). MSI
has also been found in sporadic colorectal, stomach, endometrial and ovarian cancer
samples. A literature analysis shows MSI may indicate a favorable prognosis in colorectal,
gastric, pancreatic and probably oesophageal cancers but a poor prognosis in non small cell
lung cancer. In clinical studies colorectal cancers demonstrating MSI respond better to
chemotherapy while in vitro studies using MSI positive cell lines show resistance to
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radiotherapy and chemotherapy (Lawes et al. 2003).

Microsatellite integrity in the genome is believed to be maintained by the mismatch repair

(MMR) system, which corrects single base mismatches and insertion-deletion loops on the
nascent DNA strand (Kunkel 1995). It is generally accepted that MSI is largely attributable
to the failure of repairing insertion-deletion loops arising from replication slippage
(Genschel et al. 1998).

C. CIN
Chromosome instability describes an increased rate of chromosome missegregation in
mitosis resulting in an incorrect chromosome number and/or abnormal chromosome

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structure (Rao et al. 2009). Although CIN has been long recognized as a hallmark of a
majority of tumors, it remains inconclusive if CIN is an early step or a final demonstration
of cancer progression.
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Equal segregation of chromosomes during mitosis is pivotal for the maintenance of genomic
stability. Failure of accurate chromosome segregation inevitably leads to cell death or
malignant transformation. Accurate chromosome segregation during cell division is
monitored and safeguarded by several closely linked yet distinctly different molecular
machineries.

III. CARE TAKER GENES AND PATHWAYS INVOLVED IN GENOMIC

STABILITY MAINTENANCE
A. DNA Damage Check Point
The p53 tumor suppressor serves as a central node in a complex signal transduction network
known as the p53 pathway, which has evolved as a major defense barrier against cancer.
This pathway recognizes diverse forms of oncogenic stress within the cellular environment
and translates them into appropriate cellular responses to minimize tumorigenic
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consequences. In response to stress, p53 halts cell proliferation to prevent the propagation of
DNA damage and/or directly helps in its repair. Activated p53 induces programmed cell
death (apoptosis) or senescence as a last attempt to avoid possible malignant transformation
when the damage is too severe and beyond repair. (Efeyan et al. 2006, Zhang et al. 2011).

The ataxia telangiectasia-mutated (ATM) protein is a cellular serine/threonine kinase that

plays a key role in mediating the cellular response to DNA damage (Bhatti et al. 2011). In
response to DNA damage, ATM gets phosphorylated at Ser-1981 and activated. The
activated ATM phosphorylates multiple substrates including p53, γH2AX and Chk2 (Smith
et al. 2010). ATM-mediated phosphorylation of p53 on serine 15 plays a critical role in
activating p53 function in response to DNA damage (Zhang et al. 2011).

p53 not only responds to DNA damage but also oncogenic stress. This reaction is through its
upstream p19Arf and MDM2 pathway. Arf is not usually expressed in normal tissues but is
induced by sustained and elevated proliferation signals that may stem from oncogenic stress
(Lowe and Sherr 2003). For example, physiologic thresholds of Myc and Ras signaling do
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not activate Arf gene expression, but overexpression of Myc and oncogenic Ras induces Arf
(Palmero et al. 1998, Zindy et al. 1998). Induced Arf then antagonizes Mdm2 activity to
stabilize p53 which leads to cell cycle arrest or apoptosis. This process counteracts
oncogenic proliferation signaling by inducing growth arrest or apoptosis in cells that might
otherwise give rise to tumors.

B. DNA Repair Pathway

DNA damage may predispose individuals to increased tumorigenesis when left unchecked.
Therefore, there are multiple evolutionarily conserved pathways within cells that respond to
such errors by recruiting DNA repair processes or initiating apoptosis. The process of DNA
repair is closely coupled with the DNA damage response (DDR), which involves the

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recruitment and localization within distinct nuclear foci of DNA damage sensors, mediators,
transducers and effecter proteins (Polo and Jackson 2011). Currently, several DNA repair
pathways are known to be recruited following DNA damage. In general, can be listed as
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nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR),
DNA double strand break repair (DSBR).

The nucleotide excision repair (NER) involves more than 25 proteins that function to replace
modified nucleotides with the correct ones(Mitchell et al. 2003). DNA lesions formed by
UV light, exogenous chemicals such as benzo (a) pyrene, aflotoxin B1, and
chemotherapeutic agents like cisplatin are usually repaired by the nucleotide excision repair
system. NER operates through several steps involving recognition of the lesion site, incision
of the damaged DNA strand, DNA synthesis, and finally ligation of the uncoupled flanks by
specific ligase enzymes (Mitchell et al. 2003). Three distinct NER pathways, namely, global
genomic repair (GGR), transcription-coupled repair (TCR), and differentiation-associated
repair (DAR) have been identified (Nouspikel et al. 2006). Of these, GGR pathway
functions by repairing nearly all damaged sites in the whole genome, whereas TCR is solely
involved in removal of the lesions that block the transcription of the constitutively expressed
genes (Tornaletti and Hanawalt, 1999). Each component of the NER pathway is important in
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achieving successful repair of the injured sites. Functional genetic defects in the genes of
NER-associated proteins are found to be related to certain diseases such as xeroderma
pigmentosum, Cockayne's syndrome, Trichothiodystrophy, and various types of cancers
(Lindahl, 1974; de Boer and Hoeijmakers, 2000).

The base excision repair (BER) mechanism is based on replacement of the modified bases
via deamination, methylation, and oxidation with the correct ones (Lindahl 1974). Modified
bases are removed by specific DNA glycosylase enzymes that function in specific
recognition and excision of the structurally changed bases from the genome. Apurinic/
apyrimidinic sites are formed following excision of the bases, and the correct bases are
rapidly synthesized by polymerase delta/epsilon. Finally, remaining free ends are faithfully
ligated by ligase enzymes (Jaroudi and SenGupta 2007).

The mismatch repair (MMR) system especially functions in removing base mismatches
formed by exogenous and endogenous agents that cause base deamination, oxidation, and
methylation. Moreover, the MMR system plays a role in repairing the base-base mismatches
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derived from insertions/deletions and replication errors. Replication errors are made by
DNA replication machinery that incorporates approximately one wrong nucleotide per 107
additions. Unfortunately, about 0.1% of mistakes generated by DNA replication machinery
cannot be repaired by MMR and may lead to genetic mutations (Li G. M. 2008). MMR
system comprises basic steps including recognition of the DNA lesion, strand
discrimination, excision and repair. MutS and MutL proteins participate in detecting the
mismatched bases in prokaryotic cells. Similar to prokaryotic cells, MutS (MSH1–6, MLH1
and MLH3) and MutL (PMS1 and PMS2) homologues are reported to be responsible for
recognizing the mismatched sites. The heterotetrameric complex created by the interaction
of two different MutS and MutL homologues proteins detects the mismatched bases and
certain loop structures (Sengupta et al. 2007). Following that, the mismatched base pairs are

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excised by exonucleases I enzyme, and then missing nucleotides are correctly synthesized
by polymerase δ enzyme (Modrich 2006).
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DNA double strand breaks are repaired by the DNA double strand break repair (DSBR)
system. There are two major DSB repair pathways, one is called nonhomologous end joining
(NHEJ), in which broken DNA strand ends are ligated by specific ligase enzymes; the other
is called homologous repair (HR). Since the NHEJ pathway lacks a homologous sequence
control system, it is recognized as error-prone. Deletion, inversion, and other types of
abnormalities in the genome could occur as a consequence of the NHEJ repair process (You
et al. 2009). On the other hand, HR operates in an error-free manner as it repairs the broken
ends dependent on the homologous DNA sequence (Jackson 2002). Which of the two
pathways is chosen is basically determined by whether KU (KU70 and KU80) or RAD52
binds to the damaged region. The HR pathway initiates when the KU protein interacts with
the damaged site. If the RAD52 binds to the broken ends prior to KU, the NHEJ mechanism
is commenced to repair the damage (Bassing and Alt 2004).

Breivik and Gaudernack have proposed that in some tissues during some conditions, the cost
of DNA repair might exceed the cost of errors (Breivik and Gaudernack 1999, 2004). This
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model predicts that genetic stability is configured for an optimal cost-benefit relationship;
meaning natural selection is not expected to have produced the best genetic stability
available in the human body, but only the best compromise of DNA repair and the cost of
these systems. In tissues where proliferation rates are critical, such as the colon epithelium,
any repair mechanism that delays cell division might be disadvantageous for the function of
that organ.

C. Mitotic Checkpoint
In order to maintain chromosomal stability during cell division, eukaryotic cells have
evolved a number of surveillance mechanisms termed checkpoints that monitor completion
of essential molecular and cellular processes of one stage before entering another. The
mitotic checkpoint monitors the completion of bi-orientation attachment of spindle
microtubules to all condensed chromosomes before initiation of nuclear division during
mitosis. A number of conserved proteins have been identified and characterized that are
required for the checkpoint function. These proteins include Bub1, Bub3; Mad1, Mad2 and
Mad3 (Cahill et al. 1998, Hoyt et al. 1991, Li R. and Murray 1991, Olesen et al. 2001, Weiss
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and Winey 1996). In addition to the orthologs of Bub and Mad families that consist of core
components of the spindle checkpoint in mammalian cells, several additional gene products
including Shugoshin, Aurora B, Plk1 and PP2A also play a role in spindle checkpoint
control (Dai J. et al. 2006, Mistry et al. 2010, Resnick et al. 2006, Riedel et al. 2006, Takaki
et al. 2008, Yao et al. 1997).

Bub1 is a serine/threonine protein kinase functioning as a master organizer of the inner

centromeric region (ICR), required for recruitment of chromosomal passenger complex and
Shugoshin to ICR (Roberts et al. 1994, Taylor and McKeon 1997). Bub1 promotes the
assembly of outer kinetochore components including CENP-F and BubR1 (a yeast Mad3
homolog) during the cell cycle (Boyarchuk et al. 2007). An analysis of 6 cultured CIN cell
lines (SW480, HT29, V400, V429, Caco2, and SW837) shows that some of the tested CIN

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cell lines carried certain mitotic checkpoint genes mutation and all of them had a phenotype
similar to that seen in yeast cells with genetic alterations of mitotic checkpoint genes(Cahill
et al. 1998). Such results are consistent with the possibility that aneuploidy can be due to
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defects in mitotic checkpoint. This possibility is also supported by the fact that the
expression of naturally occurring hBUB1 mutants converted the normal checkpoint status of
MSI cells to the defective type characteristic of CIN cells (Cahill et al. 1998). However, a
screen for mutations of the mitotic checkpoint genes hBUB1, hBUB1B, hBUB3 and TTK in
six aneuploid bladder cancer cell lines and 15 human bladder tumors didn't detect mutations;
loss of heterozygosity (LOH) for these genes was 6.7% of the cases; indicating that neither
mutational inactivation or LOH of these mitotic checkpoint genes are common(Olesen et al.
2001).

Shugoshin, meaning “Spirit Guardian” in Japanese, serves as a protector of the centromeric

cohesion in the yeast and high eukaryotes (Kitajima et al. 2004, Rabitsch et al. 2004).
Suppression of Shugoshin function results in premature separation of sister chromatids in
mitosis (Lee J. et al. 2008, McGuinness et al. 2005). Depletion of Sgo1 through RNA
interference (RNAi), a family member of Shugoshin, results in the formation of extra
centrosomal foci and premature separation of paired mother and daughter centriols (Wang et
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al. 2008); indicates Shugoshin gene functions in centrosome dynamics during the cell cycle
(Wang et al. 2008). In consistent with Shugoshin's role in the suppression of CIN, its
deregulated expression and/or activity have been found in malignant transformation and
tumor development. An analysis of genes deregulated in breast cancers shows that BR-85
mRNA, which codes for human Sgo1, is over-expressed in a majority of breast cancer
tissues tested and that serum antibodies against NY-BR-85 are also detected in breast cancer
patients (Scanlan et al. 2001). A separate study reveals that human colorectal cancers with
Sgo1 down-regulation exhibit a clinicopathological character of chromosomal instability
(Iwaizumi et al. 2009). Moreover, a novel SGOL1 variant has been detected in human colon
cancer (Kahyo et al. 2011). This transcript skips exon 3, leading to an early termination of
the open reading frame within exon 4 (Kahyo et al. 2011). Haploinsufficiency of SGO1
results in CIN manifested as mis-segregation of chromosomes and formation of extra
centrosomal foci in both murine embryonic fibroblasts and adult bone marrow cells
(Yamada et al. 2012). Enhanced CIN observed in SGO1-deficient mice is accompanied by
an increase in formation of aberrant crypt foci and tumor development after exposure to
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azoxymethane (AOM), a colon carcinogen (Yamada et al. 2012).

Aurora B is a member of the conserved protein kinases of the Aurora family (Carmena and
Earnshaw 2003). It is also characterized as a chromosome passenger protein which mediates
mitotic checkpoint functions during mitosis (Adams et al. 2001, Nigg 2001). The kinase
activity of Aurora B is required for stable activation of the spindle checkpoint; more
importantly, Aurora B is primarily responsible for phosphorylation of histone H3 serine 10
(H3S10) during mitosis (Carmena and Earnshaw 2003). In fact, H3S10 phosphorylation is
the major mitosis-specific phosphorylation of histone molecules and is thought to play a role
in super-condensation and supercompaction of chromosomes during mitosis in higher
eukaryotic cells (Johansen and Johansen 2006).

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Polo like kinases are named after POLO, a gene encoding a protein serine/threonine kinase
in Drosophila (Dai W. et al. 2002). Plk1 is the best characterized member of the Polo kinase
family. Depletion of Plk1 results in mitotic arrest that is partly due to alterations of
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important cell cycle molecules including anaphase promoting complex/cyclosome (APC/C)

(Dai W. et al. 2002). During prophase, Plk1 is also involved in controlling so-called the
“prophase pathway” that regulates arm cohesion of sister chromatids through direct
phosphorylation of Scc1, an integral component of the cohesin complex (Wang and Dai
2005). Cohesin not only plays a major role in the regulation of sister chromatid cohesion
during the cell cycle but also functions as a transcriptional insulator for the genome (Wendt
and Peters 2009).

Protein phosphatase 2A (PP2A) exists primarily as a heterotrimeric complex which is

composed of the scaffolding A subunit (PP2A-A), the variable regulatory subunit B (PP2A-
B), and the catalytic subunit (PP2A-C) (Ingebritsen and Cohen 1983). As a serine/threonine
phosphatase, PP2A regulates numerous molecular processes through dephosphorylating
various substrates (Shi 2009). Recent studies indicate that PP2A also localizes centromeres
during mitosis and that its activity is essential for the maintenance of centromeric cohesion
of sister chromatids before anaphase entry (Clarke et al. 2005, Kitajima et al. 2006, Riedel et
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al. 2006, Tang et al. 2006).

D. Telomere Maintenance
Human telomeres are composed of TTAGGG tandem DNA repeats with associated proteins.
Telomeres form caps that keep the ends of chromosomes from being recognized as double
strand breaks, thereby prevent chromosome fusion (Holliday 2012, Londono-Vallejo and
Wellinger 2012). In human, telomeres are maintained in germ cells, and shortened when
somatic cells divide which limits cell proliferation. This is achieved by down regulation of
telomerase. It's not a surprise to find that cancer cells at high proliferation rate can
successfully maintain the length of their telomeres, most often through the expression of
telomerase, only 10% of human tumors maintain telomeres through an alternative
mechanism (Reddel and Bryan 2003). However, cancer cells exhibit a high rate of telomere
loss at the same time, even with high levels of telomerase. A critical feature of the
spontaneous telomere loss in cancer cell lines is that it occurs at a low enough frequency so
that the cells do not die. Telomere loss contributes to chromosome instability and tumor cell
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progression (Fouladi et al. 2000, Lo et al. 2002, Sabatier et al. 2005). Excessive telomere
shortening prior to the expression of telomerase can lead to chromosome fusion, which has
been proposed as a mechanism for chromosome instability (Maser and DePinho 2002).

Mouse model with a depletion of the RNA component of telomerase (mTERC) exhibit
progressive telomere shortening and ultimately chromosomal instability (end-to-end fusions)
as a result of ageing and successive generational mating (Lee H. W. et al. 1998, Rampazzo
et al. 2010). Telomere shortening in ageing mTERC−/− mice is associated with increased
rates of cancer, suggesting that the genetic instability associated with telomere dysfunction
can facilitate transformation in vivo(Rudolph et al. 1999). On the other hand, in cultured
human cells, high level expression of telomerase facilitates malignant transformation (Hahn
et al. 1999).

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IV. HYPOTHESES OF EARLY STEPS IN TUMOR PROGRESSION AND THEIR

SUPPORTS
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With the research techniques dramatically improved, more gene mutations, gains and losses
in human tumors are found. They are usually large and chromosome rearrangements often
encompass many genes that do not contribute to tumorigenesis. Therefore, differentiating
“driver” from “passenger” requires validation.

A. Loss of Gene Function Leads to Mutator Phenotype

The mutator phenotype hypothesis states that genomic instability is present in precancerous
lesions and drives tumor development by increasing the spontaneous mutation rate (Fig. 1)
(Loeb 1991, 2001). The identification of mutations in DNA repair genes in hereditary
cancers provides strong support for the mutator hypothesis (Nikitin and Luftig 2012, Singh
et al. 2012). Proponents of the mutator hypothesis attribute the genomic instability in
precancerous lesions to mutations in caretaker genes; that is, genes that primarily function to
maintain genomic stability (Loeb 1991, 2001). Indeed, in inherited cancers, germ line
mutations targeting DNA repair genes are present in every cell of the patient's body. Thus, a
single event, loss of the remaining wild type allele, would lead to genomic instability and
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drive tumor development, as predicted by the mutator hypothesis.

Another example illustrating this point of view is Bloom syndrome, which results in an
increased predisposition to spontaneous tumor formation in all tissues, even those that are
not directly exposed to tumorigenesis insults. Bloom syndrome is caused by inactivation of a
RecQ helicase family, which plays an important role in resolving HR intermediates and
controlling blocked replication forks, as well as telomere maintenance (Singh et al. 2012).

A series of mutation screening of familial breast cancer patients and Fancony anemia
patients who are charactized by chromosome instability has found mutations in CHEK2,
ATM, NBS1, RAD50, BRIP1, and PALB are associated with doubling of breast cancer risks.
Among these genes, most are involved in the DDR pathway (Walsh and King 2007).

The study of viral infectious cancer etiology show some support to the mutator phenotype
hypothesis from chromosome instability point of view. In this case, virus infection
attenuates mitotic checkpoint and DDR pathway, causing chromosome instability in
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precancerous lesions. Accumulated aneuploid cells have the potential to promote

tumorigenesis (Nikitin and Luftig 2012). Several viral proteins precisely target mitotic
checkpoint with potentially catastrophic consequences on the chromosome stability of
surviving cells. HTLV-1 Tax abolishes host cell mitotic checkpoint by directly targeting and
prematurely activating the APC/C (Liu et al. 2005), as well as Mad 1 resulting in highly
aneuploid cells (Jin et al. 1998). Similarly, the Epstein-barr virus protein EBNA3C is
capable of decreasing the levels of the mitotic checkpoint protein BubR1 (Gruhne et al.
2009, Leao et al. 2007). However, virus infection usually affects multiple machineries in
host cells. These altered machineries act in concert to help virus proliferate, just like what
has been found in cancer cells.

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B. Oncogene Induced DNA Replication Stress Model

Oncogene induced DNA replication stress model argue against the mutator phenotype model
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by putting oncogene rather than mutation of genome care taker genes as the driving force of
tumor initiation (Fig. 2). The barriers against tumor initiation can be categorized into (1)
activation of the DNA damage checkpoint and thereby induce apoptosis or cell cycle arrest
(Bartkova et al. 2005, Gorgoulis et al. 2005) (2) Arf- mediated oncogene-induced
senescence (Braig et al. 2005, Zindy et al. 1998). From oncogene induced DNA replication
stress model, the genomic instability is first generated by DNA replication stress due to
elevated proliferation rate. The cells lack of any of these two barriers will be selected due to
their growth advantage thereby develop an even larger scale of genomic instability.

This idea is supported by evidence that uncontrolled E2F activity activates an ATM-
dependant growth-suppressive DDR, which means elevated DNA replication indeed induces
stress which is responded by DDR(Powers et al. 2004, Rogoff et al. 2004). An in vitro
model based on the critical roles of AR in prostate development and tumor progression
shows that abnormally activated growth signal is able to induce DNA breaks and genomic
instability rapidly(Lin et al. 2009). Nevertheless, Halazonetis group has shown that
expression of oncogenes leads to DNA replication stress and genomic instability, explaining
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the high frequency of p53 mutations in human cancers (Gorgoulis et al. 2005, Negrini et al.
2010).

V. DNA PROMOTER METHYLATION AND HISTONE MODIFICATION

The hypotheses and evidence considering genomic instability discussed above might be
overrated and yet underrated. The mutations found in these genes and pathways may not be
potent enough to impair protein function thereby induce genomic instability, yet epigenetic
change alone is enough to dramatically change functional protein level for genome integrity
maintenance. Hypermethylation and/or hypomethylation of promoter or first exon of cancer
related genes (tumor suppressor genes or oncogenes) may mimic the effect of mutations.

Long interspersed nuclear element (LINE) is a kind of retrotransposon. During

retrotransposition, LINE DNA is transcribed to RNA and processed. The processed RNA is
reverse-transcribed by the LINE-1 encoded reverse transcriptase and the cDNA copy is
inserted into a new chromosomal location(Luning Prak and Haoudi 2006). LINE is heavily
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methylated in all cell types in mammals. Hypomethylation of LINE induces transcriptional

activation of these sequences, which contributes to genomic instability and facilitates tumor
progression. The methylation of CpG dinucleotides in LINE and other retrotransposon
sequences hosts defense against retrotransposon activation (Bestor 2000).

Accumulating evidence indicates that remodeling of chromatin structures are crucial for
establishing stable epigenetic states that restrict or permit chromosome rearrangements in a
number of diseases such as cancer and other syndromes involving chromosomal
instability(Bartova et al. 2008, Slotkin and Martienssen 2007). In eukaryotic cells, chromatin
structures are dynamic and need to be constantly altered to accommodate DNA replication,
gene transcription and stress responses. Alterations in the interaction between DNA and
histones, together with the recruitment of nuclear proteins, cause changes in the chromatin

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structure, a process which is commonly referred to as chromatin remodeling (Hogan and

Varga-Weisz 2007). Histone tails are subject to multiple post-translational modifications
such as phosphorylation, methylation, acetylation, and ubiquitination. It has been suggested
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that the combination of these distinct covalent modifications of histones constitutes the “the
histone code” that regulates a variety of cellular processes, including mitosis and meiosis
(Xu et al. 2009). Covalent histone modifications are essential for chromatin remodeling and
they also impact mitosis through modulation of the activity and subcellular localization of
proteins important to spindle checkpoint regulation (Koch et al. 2008, Perera and Taylor
2010, Yamagishi et al. 2008). For example, tri- methylation of histone H3 lysine 9 (H3K9)
is tightly related to heterochromatinization (Elgin 1996) and recruitment of checkpoint
proteins to centromeres (Koch et al. 2008, Perera and Taylor 2010, Yamagishi et al. 2008).
Recent studies have shown that many of the components that are critical for spindle
checkpoint control such as Bub1, are also involved in regulating chromatin remodeling
(Kawashima et al. 2010). In fact, these proteins seem to coordinate histone modifications
and chromatin remodeling with cell cycle progression during mitosis.

VI. CONCLUSION REMARKS

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In spite of tremendous knowledge we've accumulated about genomic integrity, the

ubiquitous mechanism of tumor initiation still remain elusive. It's still possible that all the
hypotheses are valid in different settings. Despite of the unsettled debate of “driver” and
“passenger” in tumor initiation and genomic instability, the research effort has lead to
chemotherapeutic drugs used in clinical settings to target genomic instability related
molecules. Great progress has been made to explore the possibility to activate checkpoints
that monitor genomic integrity.

Acknowledgement
We would like to thank Nedda Tichi for her administrative assistance. This work was supported by NIEHS
ES000260

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Figure. 1. Mutator phenotype hypothesis

Mutator phenotype hypothesis states that genomic instability drives tumor development by
increasing the spontaneous mutation rate.

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Figure. 2. Oncogene induced DNA replication stress model

Oncogene induced DNA replication stress model argue against the mutator phenotype model
by putting oncogene rather than mutation of genome care taker genes as the driving force of
tumor initiation.

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