Biology Reference
In-Depth Information
Once functional TE RNAs are produced, the next defense mechanism
targets transcripts stability. The implementation of the cellular machinery to
reduce steady-state L1 mRNA levels has been shown through several experi-
mental systems. One such system implicated siRNA production from the anti-
sense L1 transcripts generated by the reverse L1 promoter itself. Endogenously
expressed L1 siRNAs were detected in human cells. This regulation through
RNA interference was reported to exhibit a twofold effect on L1 expression.
Another example of L1 mRNA regulation was shown in transgenic animals
lacking PIWI protein. The lack of functional piRNA (or rasiRNA) pathway
resulted in multifold upregulation of endogenous retroviruses and L1 elements
through their effect on methylation (Kuramochi-Miyagawa
, 2008). In later
studies, siRNA against PIWI in cultured human cells was shown to lead to the
upregulation of endogenously expressed L1 transcripts (Lin
et al.
, 2009).
Becauseverylittleisknownabout production of human L1 proteins,
particularly the ORF2 protein, some conflicting mechanisms controlling L1 transla-
tion have been put forward (Alisch
et al.
et al.
, 2006; Dmitriev
et al.
, 2007; Leibold
et al.
,
1990; Li
, 2006; McMillan and Singer, 1993). It is, however, known that wild-
type L1 sequence composition favors suboptimal codon usage (Han and Boeke 2004;
Wallace
et al.
, 2008b). Codon optimization of the mouse L1 element that also
eliminated the majority of polyadenylation sites present in L1 sequence resulted in
a significant increase in L1 mRNA, presumably L1 proteins, and L1 retrotransposi-
tion rate (Han and Boeke 2004). Codon optimization of the human L1 ORF2 also
lead to a measurable increase in protein production (Wallace
et al.
, unpublished
data). The L1 life cycle presumably involves steps that take place in different cellular
compartments (nucleus and cytoplasm). Almost nothing is known about the traffick-
ing of L1 mRNA, proteins, and/or RNPs and as a result little is known about targeted
intracellular trafficking (Goodier
et al.
, 2004, 2007). While the intermediate steps in
L1-mediated integration still remain poorly understood, the involvement of several
cellular proteins associated with antiviral defense and DNA repair has been reported.
The APOBEC family of proteins that function as RNA editing enzymes exhibit an
effect on L1 and Alu retrotransposition that seems to be independent of their
enzymatic activity through which they reduce viral RNA (Bogerd
et al.
et al.
, 2006; Chiu
et al.
, 2006; Stenglein and Harris, 2006).
An emerging role of cellular DNA repair machinery in L1 retrotran-
sposition is exciting because it introduces an interesting dilemma into the TE-
host relationship. On one hand, DNA repair proteins (ATM) are required for L1
mobilization (Gasior
, 2006; Hulme
et al.
, 2007; Muckenfuss
et al.
, 2006), that is, the host is assisting parasite invasion.
On the other hand, ERCC1 protein of the cellular nucleotide excision repair
(NER) pathway negatively regulates L1 retrotransposition (Gasior
et al.
, 2008)
serving a protective role against L1 assault. Hence the dependence on host
proteins for the completion of retrotransposition may serve to provide an impor-
tant avenue through which the host cell can regulate TE proliferation levels.
et al.
