Genome comprise of more than 45% of the

Genome is the blueprint
which contains all the relevant and irrelevant information which is required
for the human being for its growth and development. Earlier until the discovery
of jumping genes, relevant information in the genes was expressed in proteins
and carry out specific biological function. The perspective of genome changed
slowly after the revolutionary and ground-breaking discovery by Barbara
McClintock of mobile elements (Goodier et al, 2016). This discovery witnessed
the fluidity and dynamics of the genome which was supposed to be carried out by
the mobile genetic elements. They might play a great role in the evolution of
the genes and how their shape and function change with time.

Mostly genome contains repetitive
sequences and transposable genetic elements comprise of more than 45% of the
human genome. Transposable elements can be classified into Class I TEs or
retrotransposons and Class II TEs or DNA transposons (Rodic et al, 2013).
Around 98% of the transposable elements are retrotransposons, which are again
divided into long terminal repeats (LTRs) or retrovirus that constitute of 8%
of the human genome, and non-LTRs like long interspersed nuclear elements
(LINEs) and short interspersed nuclear elements (SINEs), which are important
players in cancer. LINE1 sequences are almost 17% of the total human genome
(Rodic et al, 2013). LINE 1 can copy and paste into a new gene location and
disrupt the gene expression of the associated gene and might be associated with
oncogenic expression leading to cancer initiation (Bratfhauer
et al, 1993; Carreira et al, 2013).

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LINE elements are
found in large number in the human genome. These elements spans around 6-8 kb
and lack long terminal repeats. LINEs are rich in adenine residues at the 3′
end. LINE is further subdivided into L1, L2 and L3. L1 are active
retrotransposons and L2 and L3 are inactive ones (Miousse et al, 2015).

 

LINE 1 spans
around 6-8 kb long and consists of RNA polymerase III promoter, 5′ untranslated
region, two non- overlapping open reading frames (ORF1 and ORF2), and 3′
untranslated region and flanked by target-specific direct repeats on the ends.
ORF1 and ORF2 span approximately 1 kb and around 4 kb respectively (Refer fig.
1). ORF1 encodes RNA-binding protein whose molecular weight is approximately 40
kDa and on the other hand ORF2 encodes 150 kDa protein with the functional
activities of endonuclease and reverse transcriptase (Refer fig. 1)(Li et al,
2014). The studies show that these two proteins ORF1p and ORF2p are important
for the retrotransposition (Luca et al, 2015).Short interspersed
nuclear elements (SINEs) belong to non- Long Terminal Repeat group. They are
non-autonomous retrotransposons and comprise of approximately 13% of the human
genome. These elements are around 100-400 base pairs long. They often contain
RNA polymerase III promoters but no genes. They do not code for reverse
transcriptase and depend on other transposable elements for the transposition.
Alu elements are the most common SINEs.

The
retrotransposition mechanism

The mechanism of
retrotransposition is quite understood but has to be studied more to reveal the
missing links and the underlying molecular mechanisms (Lee et al, 2012). The two
proteins encoded by L1, which are ORF1p and ORF2p, are necessarily required for
retrotransposition (Refer Fig. 2) (Wallace
et al, 2008). The integrase
which is endonuclease create a two single strand breaks which appears to be
double strand breaks at the integration site, which is AT rich DNA target
region (Symer DE, 2002; Gasior et al, 2006). Following this step, the RNA transcript of the transposable element gets
integrated in the new location. It acts as a primer for the reverse
transcriptase and copies RNA into cDNA (Refer Fig 2). The other end of the DNA
is joined and the important player is unknown. It is presumably detected and
repaired by DNA repair mechanism. But successful retrotransposition might pose
a great threat and can cause human diseases. It affects in the processes like
apoptosis and cell proliferation (Belgnaoui et al, 2006).

 

The integration of
L1 may cause a risk of mutation, recombination, insertion, deletion leading to
genomic instability. The insertion of L1 to the new site may likely to change
the function and nature of the gene. It can also lead to change in the
expression pattern of that particular gene- up-regulation or down-regulation
which is responsible for the initiation of the disease (Kemp et al, 2015).Transcriptional
deregulationRetrotransposons
are mobile elements and can get integrated anywhere in the whole genome. Their
insertion in regulatory region of the gene can cause the transcriptional
deregulation (Rebollo, R 2012). The gene
expression pattern might change and hence the transcription level changes. The
up-regulation or down-regulation of the gene leads to the deregulation and
causes the human diseases. These elements get inserted in exons,
introns, promoters, enhancers or silencers and may cause their defect. The
integration of these elements in exons can cause missense mutation, nonsense
mutation and splice site mutations (Sela,
N, 2010). Their insertion can also lead to the change in the
open reading frame and affect the transcription. The splice site can also get
affected and abruptly occur the new splice site. The introduction of Alu
elements in the introns alters the alternative splice site (Lev-Maor, G, 2003, Lev-Maor,
G, 2008). The introduction of the transposable
element can cause frameshift mutation or premature stop codon. These above
events lead to transcriptional deregulation.  Genomic
instabilityThe genomic
instability is the hallmark of the cancer. There are multifactorial reasons for
the genomic instability. There are DNA repair machinery and immune system which
are at their work all the time. But sometimes they fail to do their work and
lead to havoc in the molecular machinery leading to deregulation and
mismanagement.  The
retrotransposons forms the major of transposable elements and are interesting
to study because of their activity. LINE 1 elements encode two proteins ORF1p
(RNA binding protein and ORF2p (endonuclease and reverse transcriptase) which
are thought to be important for their insertion in the new location. These
elements are mobile and can be inserted inversely or in any random way. Their
integration can cause mutation or rearrangements or recombinations (Pal et al,
2011). These events lead to chromosomal rearrangements and genomic instability (Choi
et al, 2007; Ogino et al, 2008). LINE1
elements get inserted in introns or in microsatellite repeats. The
microsatellite instability is also responsible for cancer initiation (Inamura
et al, 2014). There are various studies showing microsatellite instability in
cancer progression (Marcos R. H. Este´cio et al, 2007). Microsatellite
instability is an important feature of several colorectal, stomach, endometrium,
ovary, urinary tract, skin, and brain cancers (Menendez et al, 2007; Negrini, S,
2010; Baba et al, 2010; Anwar, 2017).
Insertion of transposable elements is
known to alter the transcription pattern of the target gene. We have discussed
this in previous paragraph. During replication and transcription, DNA repair
system works but due to their inability, chances of DNA damage increases (Negrini,
S, 2010). The DNA damage and transcriptional deregulation are responsible for
genomic instability and hence the cancer (Valeri, N,
2010; Conti, A.; Carnevali, 2015; Daskalos
et al 2009; Wolff et al, 2010; Belancio et al, 2010b). Carcinogenesis  elements are present in the whole genome and
are more supposed to more than 45% of the genome. Earlier till their discovery,
they were considered as junk DNA. But their discovery witnessed the phenomenal
event: they can transfer anywhere in the whole genome. The retrotransposons,
which include LINE 1 and Alu elements, transfer as RNA transcript. LINE1 is
autonomous whereas Alu elements are non-autonomous depends on LINE 1 for their
activity (Rodriguez et al, 2008).  Due to stress and environmental change,
the epigenetics of the genomic DNA changes in the individuals (Refer Fig. 3).
Especially methylation pattern of the genomic DNA alters and increases the
chance of human diseases. Several studies have shown that hypomethylation of
LINE1 causes the initiation and progression of the cancer. Hypomethylation of
LINE1 reactivates the LINE 1 and encodes for ORF1p (RNA binding protein) and
ORF2p (Endonuclease as well as Reverse transcriptase) (Refer Fig. 3). These
elements then get inserted into their target region by creating double strand
break by the endonuclease of LINE 1 (Gasior
et al, 2006).  The RNA transcript of L1 gets inserted and
changes the transcription pattern of the target gene (Refer Fig. 2). That also
led to genomic instability, transcriptional deregulation, recombination,
mutations and DNA damage (Schulz
et al, 2005; Belancio et al, 2010b; Pal et al, 2011) (Refer Fig. 3). The
retrotransposition of the retrotransposons in the target gene disrupts its
transcriptional regulation (Lee et al, 2012) (Refer Fig. 3). The up-regulation
or down-regulation of the gene affects the signalling pathway in which the
particular protein is involved. This event might activate oncogene or repress
tumor suppressor gene and initiate the cancer (Tufarelli et al, 2013).

Various cancers have caused due to
hypomethylation of the LINE 1. L1Hs expression leads to origin and progression
of some breast cancer (Bratteayr et al, 1994). LINE 1 hypomethylation was more
pronounced in higher stage carcinomas and was observed in lymph node positive
prostate carcinomas (Florl et al 2004). The
level of LINE-1 methylation in normal colonic mucosa is inversely associated
with CpG island methylation (Iacopetta et al, 2007) and is associated with
shorter survival of the patients (Ogino
et al 2008). In
hepatocellular carcinomas, hypermethylation of CpG islands, and CpG island
methylator phenotype status seems to correlate with levels of long interspersed
nuclear element-1 hypomethylation (Kim
et al 2009). DNA hypomethylation changes occur later in prostate
carcinogenesis than the CpG island (Florl et al 2004; Yegnasubramanian et al
2008). Renal cancers in particular
appear to lack LINE-1 hypomethylation (Liao et al, 2011). Clinical
trials will determine whether changes in LINE-1 methylation in plasma
DNA occur as a result of treatment with DNA methylation inhibitors and parallel
changes in tumor tissue DNA (Aparicio et al 2009). The
results showed a clear and significant linear correlation of progression of
loss of methylation LINE-1 element to progression of colorectal cancer disease
(Sunami et al, 2011; Di et al, 2011).LINE1 hypomethylation
may be an important biomarker of bladder cancer risk, especially amongst women
(Wilhelm et al, 2010; Wolff et al, 2010). Global
DNA hypomethylation has been associated with the risk of cancers of the bladder
and head/neck (Kitkumthorn et al, 2012). The strong correlation between LINE-1
methylation levels among affected father-affected son pairs suggests that
transgenerational inheritance of an epigenetic event may be associated with
disease risk (Mirabello et al, 2010). LINE-1 hypomethylation was an independent
marker of poor prognosis in stage IA non-small cell lung cancer (Saito et al,
2010).  ConclusionLINE-1 methylation could be a useful biomarker
for predicting the prognosis of the disease like cancer (Aparicio et al, 2009; Igarashi
et al, 2010; Bae et al, 2011; Tufarelli et al, 2013). The 5-FU-mediated
induction of phospho-histone H2A.X, a marker of DNA damage, was inhibited by
knockdown of LINE-1. These results suggest that LINE-1 methylation is a novel
predictive marker for survival benefit from adjuvant chemotherapy with oral
fluoropyrimidines in colorectal cancer patients. This finding could be
important for achieving personalized chemotherapy (Kawakami et al, 2010). Further
studies are needed to assess the potential of LINE-1 methylation status as a
prognostic biomarker for young people with CRC (Antelo et al, 2012; Kaneko et al, 2016).
LINE-1 hypomethylation in gastric cancer is associated with shorter survival,
suggesting that it has potential for use as a prognostic biomarker (Xiang et
al, 2011; Shigaki et al, 2012). 

In summary, TEs are junk DNA but they are
found to play a big role in human diseases like cancer. LINE 1 gets reactivated
in most of the cancers. The epigenetic modification of retrotrotransposons
activates the LINE 1 and further activates the key players in the cancer.
However, less is known about the molecular mechanism underlying the initiation
and progression of the cancer by the epigenetic modification of
retrotransposons. The epigenetic inhibitors can be used as drug targets once
the mechanism is understood.