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different human tissues and adult stem cells (Belancio
, 2010b) suggesting
tissue-specific variation in the L1-induced DNA damage. Our findings suggest
that adult stem cells as well as some human tissues may be protected from the
endogenous L1-induced DNA damage relative to other tissues due to the exten-
sive L1 RNA processing that leads to the production of retrotranspositionally
defective L1-related mRNAs (Belancio
et al.
, 2010b). Accumulation of the
L1-related DNA damage in somatic and adult stem cells with time may result
in reduced performance, or, in the case of adult stem cells, in the decreased
tissue-renewal capacity and production of differentiated progeny cells that in-
herit genomic defects accumulated in stem cells (Fig. 6.4). L1-induced DNA
damage may also increase with time due to age-related alterations in DNA repair
and other cellular pathways that control L1 activity (Barbot
et al.
et al.
, 2002;
Richardson, 2003; Seluanov
, 1987). Additionally,
the significant variation in the endogenous L1 activity estimated to exist in the
human population (Seleme
et al.
, 2004; Singhal
et al.
, 2006; Fig. 6.3) correlates with the remarkable
variation in the rate of individual aging, the length of life span, and the onset and
severity of the age-associated diseases.
With the exception of an increasing number of evolutionary advanta-
geous examples of acquisition of diverse beneficial functions by TEs within their
host genomes, the largely supported view of the TE influence on the genome
stability is that of a negative nature. While this view is applicable most of the
time to the genome of a single cell, it may only represent one side of the coin
when considering the fate of the cells that support TE expression in terms of the
overall health of the tissue and organism in which they reside. The discovery of
the L1-associated toxicity (Gasior
et al.
, 2008b) that
manifests itself in the form of apoptosis and cellular senescence in both cancer
and normal (Belancio
et al.
, 2006; Wallace
et al.
, 2010b) human cells suggests that the outcome of TE
expression needs to be considered in the context of the specific genomic envi-
ronment. While TE activity promotes genomic instability through a plethora of
mechanisms, TE-associated genomic rearrangements that can lead to the onset
or progression of disease may also trigger cell-cycle arrest, followed by elimina-
tion of aberrant cell(s) from the population. Based on the reported experimental
evidence, deregulated L1 expression, which often happens in response to some
external or internal stimuli, in cells with fully or partially functional cell cycle
check points can trigger apoptosis or senescence leading to the removal of these
cells from further propagation. Interestingly, accumulation of senescent cells in
normal tissues with age has been reported (Herbig
et al.
,
2007). On the contrary, cells defective in the DNA damage surveillance would
escape elimination and continue to exist with accumulated genetic defects. The
double-edged-sword hypothesis of L1 expression (Belancio
et al.
, 2006; Jeyapalan
et al.
, 2010a) implies
that L1, through precisely the same types of DNA damage, may play a role in
human diseases such as cancer or normal biological processes such as aging.
et al.
