Biology Reference
In-Depth Information
A. DSBs
The discovery of DSB generation by the L1 EN (Belgnaoui
et al.
, 2006; Farkash
et al.
,
2006; Gasior
,2006) introduced a possibility of the existence of genomic
damage that is likely to impose additional strain on the TE/host relationship. The
L1 EN that allows for L1, Alu, and SVA mobilization within the human genome
introduces DNA strand breakage which, when not properly resolved, can have
deleterious consequences on the host genome (Gasior
et al.
,
2008b). These breakages can involve one or both strands of the DNA backbone.
While single stranded DNA breaks can typically be repaired by the cell without
catastrophic consequences, they can, when in combination with a replication fork
or some secondary chemical insult, lead to the generation of DSBs. DSBs are known
to have detrimental effects on cells [reviewed in van Gent
et al.
, 2006; Wallace
et al.
, 2001; Vilenchik
and Knudson, 2003]. Consequently, organisms have involved an impressive pro-
tein-based surveillance system to detect and mark such breaks for repair (Abraham,
2003; Bakkenist and Kastan, 2003; Lieber, 2010). In humans, both H2AX foci
staining and comet assays have been used to demonstrate that L1 EN activity results
in the formation of DSBs in both normal and cancer cells (Belancio
et al.
et al.
, 2010b;
Belgnaoui
,2006). Such breaks were
observed to occur in excess of the number of successful insertions (Gasior
et al.
, 2006; Farkash
et al.
,2006;Gasior
et al.
,
2006). The accumulation of DSBs can initiate an arrest of the cell cycle while repair
is attempted (Gasior
et al.
,2006). If the damage is too extensive, apoptosis or
senescence will be triggered (Belancio
et al.
et al.
, 2010b; Belgnaoui
et al.
,2006;Gasior
et al.
,2008b). Even though the mutagenic potential of the L1-
induced DSBs is not known, they are expected to contribute to genomic instability
at the sites of L1 expression that, in addition to germline and tumors (Branciforte
and Martin, 1994; Bratthauer and Fanning, 1993; Bratthauer
, 2006; Wallace
et al.
et al.
, 1994; Martin
and Branciforte, 1993; Ostertag
et al.
,2002), also includes normal human somatic
tissues (Belancio
, 2010b). This assumption is based on the reports that even
when dsDNA repair is successful, genomic rearrangements resulting from the repair
process can lead to the loss or gain of genomic information and/or the disruption of
regulatory signals [reviewed invanGent
et al.
, 2001; Vilenchik and Knudson, 2003].
Thus, it is likely that L1 EN is responsible for “hidden” L1 damage previously not
associatedwith the activity of these elements. As discussed inmore detail in the
et al.
TEs
and human health
section below, when these effects occur in the germline, they have
implications for heritable genetic diseases. When they occur in the soma, there are
potential consequences for both cancer and aging.
B. Retrotransposition
While the mutagenic potential of the L1-associated DSBs has not been character-
ized, the contribution of human TEs to genomic instability through retrotransposi-
tion is well established [reviewed in Belancio
et al.
, 2009, 2010a; Cordaux and
