The Testis as a Conduit for Genomic Plasticity
APOBEC3 proteins: major players in intracellular
defence against LINE-1-mediated
retrotransposition
G.G. Schumann1
Section PR2/Retroelements, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, D-63225 Langen, Germany
Abstract
Mammalian genomes are littered with enormous numbers of transposable elements interspersed within
and between single-copy endogenous genes. The only presently spreading class of human transposable
elements comprises non-LTR (long terminal repeat) retrotransposons, which cover approx. 34% of the
human genome. Non-LTR retrotransposons include the widespread autonomous LINEs (long interspersed
nuclear elements) and non-autonomous elements such as processed pseudogenes, SVAs [named after
SINE (short interspersed nuclear element), VNTR (variable number of tandem repeats) and Alu] and SINEs.
Mobilization of these elements affects the host genome, can be deleterious to the host cell, and cause
genetic disorders and cancer. In order to limit negative effects of retrotransposition, host genomes
have adopted several strategies to curb the proliferation of transposable elements. Recent studies have
demonstrated that members of the human APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic
polypeptide 3) protein family inhibit the mobilization of the non-LTR retrotransposons LINE-1 and Alu
significantly and participate in the intracellular defence against retrotransposition by mechanisms unknown
to date. The striking coincidence between the expansion of the APOBEC3 gene cluster and the abrupt decline
in retrotransposon activity in primates raises the possibility that these genes may have been expanded to
prevent genomic instability caused by endogenous retroelements.
Destructive and constructive effects of
LINE (long interspersed nuclear
element)-1 activity
All vertebrate genomes include large numbers of retroelements which can be divided into three classes: exogenous
retroviruses, retrotransposons containing LTRs (long terminal repeats) and retrotransposons without LTRs, named
non-LTR retrotransposons. Only members of the class
of non-LTR retrotransposons are currently spreading in the
human genome, and they can be subdivided further into
autonomous LINEs and non-autonomous non-LTR retrotransposons, such as SINEs (short interspersed nuclear
elements), SVAs [named after SINE, VNTR (variable number
of tandem repeats) and Alu] and processed pseudogenes
(Figure 1A). Alu elements represent a highly active family of
human SINEs and constitute ∼11% of the entire genome [1].
LINE-1, the most common and only active human LINE,
is named autonomous because it has coding capacity for
the protein machinery required for its own transposition.
Key words: Alu, apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC),
intracellular defence, intrinsic immunity, long interspersed nuclear element 1 (LINE-1),
retrotransposon.
Abbreviations used: APOBEC, apolipoprotein B mRNA editing enzyme catalytic polypeptide;
CDA, cytidine deaminase; hA3A etc., human APOBEC3A etc.; LINE, long interspersed nuclear
element; LTR, long terminal repeat; ORF, open reading frame; ORF1p etc., ORF1 protein etc.; RT,
reverse transcriptase; SINE, short interspersed nuclear element; UTR, untranslated region; VNTR,
variable number of tandem repeats; SVA, SINE, VNTR and Alu.
1
email [email protected]
In contrast, non-autonomous non-LTR retrotransposons
lack any protein-coding capacity and have evolved refined
parasitic strategies to efficiently bypass the cis-preference of
LINE-1 for their own retrotransposition. Therefore more
than one-third of the human genome is the result, directly or
indirectly, of LINE-1 retrotransposon activity.
LINE-1-mediated retrotransposition can occur in germ
cells and/or during early embryogenesis, before the germline
becomes a distinct lineage [2,3]. Although retrotranspostion
events also occur occasionally in specific somatic cell types,
only those events that take place in cells destined for the next
generation are evolutionarily successful. LINE-1 elements
continuously alter the genome structure in many ways, both
destructive and constructive, and their activity can lead to
genomic instability and sometimes cause human disease [4–
7]. LINE-1s and Alus can be destructive by causing insertions
and by providing material for homologous recombination.
The average human diploid genome has 80–100 active
LINE-1s [8]. At least 1 in every 50 humans has a new genomic LINE-1 insertion that occurred in parental germ cells or
in early embryonic development [2,3,9]. LINE-1 insertions
account for approx. 1 in 1200 human mutations, some of
which cause disease [10–12]. LINE-1s cause genome instability by generating substantial deletions during the LINE-1
integration process [4,5]. They have a marked cis preference,
whereby their proteins greatly prefer to act on the RNA that
encodes them [13]. Nevertheless, LINE-1s are still able on
occasion to mobilize non-autonomous sequences in trans
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Figure 1 Human non-LTR retrotransposons and the APOBEC3 protein family of CDAs
(A) Structures of mobile human non-LTR retrotransposons. LINE-1, SINEs, SVAs and processed pseudogenes are characterized
by flanking target site duplications (short stippled black arrows), of varying length (usually 9–20 nt) and by a poly(A)-rich
tail. Functional LINE-1s are 6 kb long, include an internal pol II promoter in their 5 -UTR, two ORFs (ORF1 and ORF2) and a
3 -UTR. SINEs, with their most active member Alu, are short pol III-transcribed elements with an internal promoter. Processed
pseudogenes are DNA elements with the structure of a cDNA generated by reverse transcription of a cellular mRNA. A
full-length processed pseudogene is shown schematically as well as the cellular gene and the corresponding mRNA from
which the pseudogene was reverse-transcribed (in parentheses). SVA elements are composed of five modules: a (CCCTCT)n
hexamer simple repeat region; an Alu homologous region (Alu-like), usually composed of two antisense Alu fragments
and an additional sequence of unknown origin; a VNTR region; and a ∼490 bp region which is derived from the 3 end of
HERV-K10 (human endogenous retrovirus K10). (B) Domain organization of human APOBEC3 proteins. Grey bars represent
CDA motifs in each protein. The consensus amino acid sequence of the catalytic domains and the numbers of amino acids
(aa) that compose the proteins are shown. Nuclear (N) and cytoplasmic (C) localization of the proteins as well as publications
reporting major (++), modest (+) and no (−) inhibitory effects are indicated. /, not determined.
[14,15]. Trans-mobilization of Alu elements resulted in the
expansion of Alu sequences to 1.1 million copies in the human
genome. Alu insertions have accounted for over 20 cases of
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human genetic disease, and Alu retrotransposition events occur in at least 1 in every 30 individuals [10]. Processed pseudogenes and SVA elements are two other non-autonomous
The Testis as a Conduit for Genomic Plasticity
retrotransposons that are probably mobilized by human
LINE-1s [15,16].
Nevertheless, there are several effects of LINE-1 activity
that could also be constructive for the host organism.
First, LINE-1s occasionally repair double-strand breaks in
DNA by inserting into the genome via an endonucleaseindependent pathway [17]. Secondly, LINE-1 can retrotranspose non-LINE-1 DNA from its 3 flank to new genomic
locations in a process termed 3 transduction [18]. Thirdly,
retrotransposons provide their sequences for a number of
protein-coding exons of genes. In the human genome, LINE1 or Alu sequences are present in nearly 200 confirmed and
2400 predicted protein-coding sequences [19]. Fourthly,
LINE-1 retrotransposition can produce new chimaeric
retrogenes that are probably generated through template
switching of LINE-1 RT (reverse transcriptase) from LINE-1
RNA or Alu RNA to other small nuclear RNAs [20]. Fifthly,
LINE-1 retrotransposons can also affect gene expression.
They contain an antisense promoter in their 5 -UTR (untranslated region), and a number of expressed genes located
5 to full-length LINE-1s have alternative transcription start
sites in this LINE-1 region [21]. Also, intronic LINE-1 insertions in either orientation can affect the RNA production of
endogenous genes, both qualitatively and quantitatively [22].
Owing to their deleterious effects, mobile genetic elements
have been in conflict with host genomes for over a billion
years. Our own genomes reveal the remarkable effects of
retrotransposition, as approx. 45% of our genomic DNA
results directly from this process [1]. This perennial state
of conflict has led eukaryotes to adopt several strategies to
curb the proliferation of transposable elements and viruses.
These include transcriptional silencing through DNA and
histone methylation or RNA interference, and even directed
mutagenesis of mobile elements.
Several host-encoded proteins have been identified to influence LINE-1 transcription [23–27], and it has been suggested that the human LINE-1 element is susceptible to RNA
interference [28,29]. However, the modulating potential
of these factors does not sufficiently explain the well-controlled cell-type-specific LINE-1 expression and retrotransposition observed in mammals. Therefore additional hostencoded strategies were postulated to keep LINE-1-mediated
retrotransposition in check and modulate the transposition
frequency so that it is not harmful to the host.
The APOBEC (apolipoprotein B mRNA
editing enzyme catalytic polypeptide)
3 protein family
The ability of human APOBEC3 protein family members to
function as innate inhibitors of a wide range of exogenous retroviruses was first noticed during studies analysing the HIV-1
Vif protein [30,31]. APOBEC3G (hA3G), one member of the
APOBEC3 protein family, was shown to be a potent inhibitor
of Vif-deficient replication. In the absence of Vif, hA3G
is specifically packaged into progeny virion particles and
then interferes with reverse transcription during subsequent
infections [30,31]. hA3G is a CDA (cytidine deaminase) that
edits dC residues to dU on nascent DNA-minus strands
during reverse transcription [32–34]. This activity induces
extensive mutagenesis of the HIV genome and was suggested
to destabilize incomplete reverse transcripts.
APOBEC3 proteins belong to a family of CDAs with
diverse functions [35]. This family was named after the first
of these proteins to be discovered, APOBEC1. All proteins
in this family have one or two CDA motifs comprising
the sequence His-Xaa-Glu-Xaa23−28 -Pro-Cys-Xaa2−4 -Cys
(Figure 1B). Catalysis results in hydrolytic deamination at the
C4 position of the cytosine base, thereby converting cytidine
(C) into uridine (U) in a process called ‘editing’. In humans,
the APOBEC family includes AID (activation-induced
CDA), APOBEC1, APOBEC2, APOBEC3A–APOBEC3H
(hA3A–hA3H) (Figure 1B) and APOBEC4. The APOBEC3
family has expanded from one gene in the mouse to as many as
seven genes in primates [30]. APOBEC3 proteins can confer
innate immunity on a wide range of exogenous retroviruses.
Individual APOBEC3 members can also block the replication
of hepatitis B virus, and inhibit the replication of endogenous
retroviruses [30]. APOBEC3 genes are expressed in almost
every human tissue, cell type and cell line analysed so far
(Table 1). The genes encoding APOBEC3 family members
are clustered on chromosome 22 [35]. During mammalian
evolution, this locus expanded from a single gene in mice to
seven genes (hA3A–hA3H) in primates [35,36] (Figure 1B).
Inhibition of LINE-1 retrotransposition
Effects of APOBEC3 proteins on human LINE-1 retrotransposition were assessed applying LINE-1 retrotransposition reporter assays [37,38] in human HEK-293T (human
embryonic kidney), BTK-143 osteosarcoma and HeLa
cells [39–44]. Co-expression of LINE-1 reporter constructs
with APOBEC3 proteins in these cells revealed that
hA3A, hA3B and hA3F are effective inhibitors of LINE-1
retrotransposition causing a reduction of LINE-1 transposition frequency by 85–99, 75–90 and 70–80% respectively
(Figure 2) [39,42–44]. Notably, the hA3F protein used in
those experiments differs at two amino acid residues (108
and 231) from the hA3F protein used in two additional
studies, demonstrating only a negligible reduction of LINE-1
transposition by ∼20% [42] and even an increase by 30–75%
[45]. This suggests that both amino acid residues are critical
for the LINE-1-inhibiting activity of hA3F. There is also
the possibility that variations in the retrotransposition assay
used in the different studies account for the differences which
are also observed in the case of hA3C and hA3G. Although
two studies report a reduction of LINE-1 transposition by
∼75% in the presence of hA3C [43,44], a third study demonstrates an inhibition by only ∼40% [42].
In the case of hA3G, several reports show a minor decrease
by 12–20% [42–44] or no effect all [40]. Two other studies
describe an inhibition by ∼40% [39] and a negligible increase
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Table 1 Expression of APOBEC3 mRNA in human tissues and cell types
APOBEC3 expression was analysed by reverse transcription–PCR and Northern blot analysis. References reporting expression levels are indicated.
NCCIT, National Cancer Center immature teratoma; −, RNA not detectable; +, RNA detectable; ++, major amount of RNA detectable; +/−, modest
RNA expression; /, not analysed.
Expression
Tissue/cell type analysed
A3A
A3B
A3C
A3F
A3G
A3H
Pancreas
Kidney
/
/
− [35,46]
− [35,46]
+ [35]
+ [35]
+ [49]
+ [47,49]
− [35], + [49]
− [35], + [47,49]
/
/
Skeletal muscle
Liver
Fetal liver
/
/
/
− [35,46]
− [35]
− [46]
+ [35]
+ [35]
/
+ [49], − [47]
+ [47,49]
+ [49]
− [35,47,49]
− [35], + [47,49]
+ [49]
/
/
/
Lung
Placenta
Brain
/
/
/
− [35,46]
− [35,46]
− [35,46]
+ [35]
+ [35]
− [35]
+ [47,49]
+ [47,49]
− [47,49]
+ [35,47,49]
+ [35,47,49]
− [35,49]
/
/
/
Lymph node
Spleen
Thymus
/
++ [42]
− [42]
− [46]
− [35,46], ++ [42]
− [35,46], + [42]
/
++ [35]
+ [35]
+ [49]
+ [39,47,49]
+ [47,49]
/
++ [35,47,49]
+ [35,47,49]
/
/
/
Tonsil
Bone marrow
/
/
− [46]
− [46]
/
/
+ [49]
+ [49]
+ [49]
+ [49]
/
/
Prostate
Testis
Ovary
− [42]
− [42]
− [42]
− [35], + [42]
+/− [35], + [42]
+/− [35], ++ [42]
++ [35]
++ [35]
++ [35]
/
+ [39]
/
+ [35]
++ [35]
+ [35]
/
/
/
Small intestine
Colon
Heart
+ [42]
− [42]
/
+ [35,42]
++ [35,42]
− [35,46]
+
/
+ [35]
+ [47]
+ [47]
+ [47,49]
+ [35,47]
+ [35,47]
+ [47,49]
/
/
/
Keratinocytes
Macrophages
Monocytes
+ [43]
+ [44]
+ [44]
+ [43]
/
/
++ [43]
/
/
+ [43]
/
/
+ [43]
/
/
+ [43]
/
/
Peripheral blood lymphocytes
Peripheral blood mononuclear cells
B-cells
++ [42]
+ [43,44]
/
++ [35,42], − [46]
− [43,48]
− [46]
/
++ [43]
/
+ [47,49]
+ [43,48]
+ [49]
++ [35,47,49]
+ [43,48]
+ [49]
/
+ [43]
/
Activated CD4+ T-cells
Activated CD8+ T-cells
T-cell lines
− [44]
− [44]
/
/
/
/
/
/
/
/
/
/
A3.01
HUT78
/
/
− [43]
− [48]
++ [43]
/
+ [43]
+ [48]
+ [43]
+ [48]
+ [43]
/
H9
CEM
SupT1
/
/
/
− [46,48]
+ [46,48]
− [48]
/
/
/
+ [46,48,49]
+ [46,48,49]
− [48]
+ [46,48], − [49]
+ [46,48,49]
− [48]
/
/
/
CEM-SS
NCCIT
HeLa cells
/
− [44]
− [43]
− [46]
/
+++ [35,43], − [48]
/
/
++ [35,43]
− [46,49], +/− [48]
/
− [43,48]
− [46,48,49]
/
+ [35], − [43,48]
/
/
+ [43]
HEK-293T cells
Melanoma
Lung carcinoma
− [44]
/
/
/
++ [35]
++ [35]
/
++ [35]
++ [35]
/
/
/
/
+ [35]
+ [35]
/
/
/
Colorectal adenocarcinoma
Burkitt’s lymphoma Raji
Lymphoblastic leukaemia
+++ [35,46]
++ [35]
− [35]
++ [35]
++ [35]
+ [35]
+ [46]
/
/
++ [35,46]
+ [35]
− [35]
/
/
/
/
/
/
Chronic myelogenous leukaemia
Promyelocytic leukaemia
+++ [35,46]
− [35]
++ [35]
+ [35]
+ [46,49]
/
+ [35,46,49]
+ [35]
/
/
/
/
by ∼10% [41] respectively. Taken together, hA3A, hA3B,
hA3C and hA3F are major inhibitory factors of human
LINE-1 retrotransposition, whereas hA3G, hA3H and
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hA3D have only a negligible impact on LINE-1 mobilization
(Figure 2). Although initial reports on the inhibition of
mobility of diverse retroviruses and retrotransposons by
The Testis as a Conduit for Genomic Plasticity
Figure 2 Inhibition of LINE-1 retrotransposition by APOBEC3
proteins
Relative LINE-1 retrotransposition rates in the presence of APOBEC3
proteins are shown. Retrotransposition frequencies in the presence of
the empty APOBEC3 expression were set as 100% (vector). Results are
means ± S.D. for six (hA3A, hA3G and hA3H) or three (hA3B, hA3C and
hA3F) independent experiments. Reproduced from [43] with permission.
c 2006 The American Society for Biochemistry and Molecular Biology.
APOBEC3 proteins proposed that these effects were due
to the DNA-editing capabilities of these enzymes, there is no
evidence for editing-dependent inhibition of non-LTR retrotransposon mobility so far. Non-LTR retrotransposon RNA
is reverse-transcribed at the genomic integration site through
a process known as target-primed reverse transcription [12]
and thus takes place in the nucleus. The identification of
hA3A, hA3B and hA3C proteins in the nucleus (Figure 1B)
[39,42,43] would therefore be consistent with the hypothesis
of LINE-1 inhibition by DNA editing, especially because
these proteins have been shown to function as active CDAs
on other substrates [42,44,48]. However, although LINE-1inhibiting activity of hA3A was shown to be dependent on
an intact CDA site [43], inhibition by hA3B was independent
of CDA activity [39]. Also, mutations in DNA sequences
that are retrotransposed in the presence of any of the four
LINE-1-inhibiting APOBEC3 proteins (Figure 2) could not
be detected [39,42,43]. It is possible that the single-stranded
nucleic acid substrate is not available for editing during targetprimed reverse transcription or that edited transcripts are
rapidly degraded and are not available for reverse transcription and integration into the genomic DNA. The cytoplasmic
localization of hA3F is consistent with a LINE-1-inhibiting
mechanism that does not interfere with reverse transcription.
Inhibition of Alu retrotransposition
Retrotransposition of Alu elements is mediated by the LINE1 ORF 2p [ORF (open reading frame) 2 protein] (Figure 1A)
[14], which has RT and endonuclease activities [12], but
does not require the LINE-1 ORF1 RNA-binding protein
[14]. hA3A, hA3B and hA3G acted as potent inhibitors
of Alu retrotransposition causing a 75–90% reduction of
transposition frequency regardless of whether ORF2p alone
or both ORF1p and ORF2p were expressed [42,45,50].
The inhibition of Alu retrotransposition by hA3G, a
protein that does not affect LINE-1 retrotransposition, is
surprising [45,50]. The fact that an active CDA site is not
required for restriction of Alu retrotransposition by hA3G
implies that at least hA3G clearly inhibits Alu retrotransposition independent of hypermutation [45,50]. It has been
suggested that hA3G achieves this inhibition by sequestering
Alu RNA in cytosolic ribonucleoprotein complexes, where it
is unavailable for targeting by the LINE-1 RT and thus cannot
be reverse-transcribed [50]. This would imply that the inhibitory mechanism inflicted by hA3G is not only distinct from
editing, but also differs from the hA3A- and hA3B-mediated
inhibition that has been proposed to target Alu elements indirectly by inhibiting the LINE-1 transposition machinery. This
possibility seems to represent one example for a mechanism
of editing-independent inhibition of retroelement mobility.
Taken together, evidence is accumulating that the
APOBEC3 family of CDAs can inhibit retroelements by several mechanisms, including editing-dependent and editingindependent processes. It is striking that mice which are
equipped with only one single APOBEC3 gene carry
50–60 times more active LINE-1 elements in their genomes
compared with humans and that the proportion of LINE-1
insertions causing mouse disease is also approx. 35-fold
higher [10]. The observation that the abrupt decline in
retrotransposition activity in primates coincides with the
expansion of the APOBEC3 gene cluster during evolution
implies an essential role of APOBEC3 proteins in the
protection of host genomes from invading mobile DNA.
I thank Carsten Münk for comments on this manuscript. Work in my
laboratory is supported by the Deutsche Forschungsgemeinschaft
(DFG).
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