A3C tarkemmin selvitettynä transposonien hallinnan suhteen

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874205/

Nucleic Acids Res. 2014 Jan 1; 42(1): 396–416.

Published online 2013 Oct 5. doi:  10.1093/nar/gkt898

PMCID: PMC3874205

PMID: 24101588

Human LINE-1 restriction by APOBEC3C is deaminase independent and mediated by an ORF1p interaction that affects LINE reverse transcriptase activity

Axel V. Horn,^1,2 Sabine Klawitter   et aliae

Citate..."  LINE-1 (L1) retrotransposon activity can cause disease by insertional mutagenesis, recombination, providing enzymatic activities for other non-long terminal repeat (non-LTR) retrotransposons, and perhaps by transcriptional over-activation and epigenetic effects [reviewed in (1,2)]. Since L1 elements were discovered as mutagenic insertions in 1988 (3), 96 disease-causing mutations in humans have been attributed to L1-mediated retrotransposition events [reviewed in (4)]. Recent reports also suggest that L1 endonuclease may have a general function in facilitating chromosomal breaks and genome instability (5,6).

 To limit such deleterious effects of retrotransposition, host genomes have adopted several strategies to curb the proliferation of transposable elements. Mechanistic strategies used by the host to restrict the mobilization of transposable elements include DNA methylation (7–9), small-RNA–based mechanisms (10–12), DNA repair factors (13,14) and L1 restriction by TREX1 DNA exonuclease (15) and members of the human APOBEC3 (Apolipoprotein B mRNA Editing Enzyme Catalytic Polypeptide 3, A3) protein family of cytidine deaminases [reviewed in (16)]."

The human A3 protein family comprises seven members that include either one (APOBEC3A [A3A], APOBEC3C [A3C], APOBEC3H [A3H]) or two (APOBEC3B [A3B], APOBEC3D [A3D], APOBEC3F [A3F], APOBEC3G [A3G]) cytidine deaminase (CDA) domains containing a conserved zinc-binding motif (C/H)-X-E-X_23-28-P-C-X_2-4-C (17–20).

 Multiple A3 genes were reported to be expressed constitutively in most types of cells and tissues (21).

A3 proteins can restrict the replication of various retroviruses and LTR retrotransposons by deaminating cytidines during the first-strand complementary DNA (cDNA) synthesis, which leads to either cDNA degradation or the integration of a mutated provirus or LTR retrotransposon, respectively (22,23).

 All A3 enzymes exhibit specificity for single-stranded DNA. Since the reaction product is deoxyuridine, A3 activity results in DNA peppered with C→U substitutions, referred to as hypermutants. The degree of editing can range from a few cytidine targets per kilobase to ∼90% of all cytidine residues (24–31). All A3 enzymes preferentially edit single-stranded DNA when the edited base is 5′-flanked by thymidine or cytidine, i.e. TpC and CpC [summarized in (32)].

 However, recent studies have provided evidence suggesting that A3 proteins can inhibit retroviruses by editing-independent processes (33). For instance, antiviral activities of wild-type (WT) and catalytically inactive A3F and A3G proteins were reported to correspond well with reductions in the accumulation of viral reverse transcriptase (RT) products (34)."
 ..
" A3C is the most abundantly expressed of all the A3 genes across a wide range of tissues (17)."
 ..

"DISCUSSION

Higher eukaryotes have evolved various defense mechanisms to protect their genomes from potential mutagenic effects caused by uncontrolled proliferation of transposable elements. Members of the A3 protein family were reported to inhibit L1 and/or Alu retrotransposition by 30–99% [reviewed in (23,74)]. However, no direct evidence for the inhibition of the currently mobilized L1Hs subfamily by cytidine deamination of L1Hs cDNA or any kind of editing of L1 nucleic acid sequences has yet been reported. This strongly suggests that CDA-independent mechanisms are involved in A3-mediated L1 restriction. Since A3C is the most abundantly expressed A3 protein across a wide range of human tissues and cells, we set out to elucidate the A3C-mediated mechanism of L1 restriction.  .."