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In-Depth Information
significantly changes requirements for Alu mobilization (Kroutter
, 2009).
Similarly to the L1 and SVA elements, Alu RNAs contain a polyA tail at their 3
0
end, but in contrast to the polyA tails of L1 and SVA, it is encoded within
genomic Alu sequences rather than being generated through polyadenylation by
cellular proteins.
Mammalian L1 elements encode two proteins, open reading frame 1
(ORF1) and open read frame 2 (ORF2), that are absolutely essential for L1
retrotransposition (Fig. 6.1). L1 ORF1 and ORF2 proteins are presumed to be
made in the cytoplasm of the cells that permit transcription of a full length,
bicistronic L1 mRNA. Very little is known about L1 mRNA translation and
even less about the mechanisms that may regulate L1 protein production (Alisch
et al.
et al.
, 2006; McMillan
and Singer, 1993). Extensive empirical evidence points out that L1 ORF1 plays a
crucial role in the formation of ribonucleoprotein (RNP) complexes with L1
mRNA that are believed to represent important retrotransposition intermediates
(Kolosha and Martin, 1997, 2003; Kulpa and Moran, 2005; Martin, 1991; Martin
et al.
, 2006; Dmitriev
et al.
, 2007; Leibold
et al.
, 1990; Li
et al.
, 2000). L1 ORF2 is also associated with the L1 RNPs (Kulpa and Moran,
2005; Wei
, 2001) and these L1 RNA/protein complexes gain access by an
undefined passive or active mechanism to genomic DNA. L1 ORF2 contains
apurinic-like EN and RT domains that are responsible for a series of sequential
enzymatic steps in the LINE, SINE, and SVA integration process (Clements and
Singer, 1998; Cost and Boeke, 1998; Cost
et al.
et al.
, 2002; Feng
et al.
, 1996; Martin
et al.
, 1998). While the requirement for the functional L1 ORF2 is shared by all
three non-LTR retroelements (LINEs, SINEs, and SVA), L1 ORF1 protein has
been reported to be indispensable only in the case of L1 mobilization
(Dewannieux
, 1996). Currently there is very limited
understanding of how, when, and where Alu and SVA RNAs hijack the L1
ORF2 protein. The means of gaining access to L1 ORF2 by SINEs and SVAs are
complicated by the existence of a very strong cis-preference of L1 proteins for the
specific L1 mRNA instance that was the source of their translation (Wei
et al.
, 2003; Moran
et al.
,
2001). This cis-preference may be one of the mechanisms that serve to prevent
retroelements from wreaking havoc in the host genome through mobilization of
otherwise retrotranspositionally incompetent TE RNAs and normal cellular
transcripts resulting in the bombardment of the human genome with retro-
pseudogene copies. Nevertheless, despite the apparent barriers to commandeer-
ing the L1 mobilization apparatus, both SINEs and SVA elements have been
extremely successful at doing so (Lander
et al.
, 2005),
suggesting a potential active mechanism of gaining access to the L1 ORF2.
Alu elements have been particularly adept at this process, which is likely one
of the reasons that allowed them to flourish to over 1,000,000 copies in the
human genome surpassing L1 copy number by more than a half (Lander
et al.
, 2001; Wang
et al.
et al.
,
2001).
