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Apolipoprotein B mRNA‐editing, catalytic polypeptide cytidine deaminases and retroviral restriction

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Abstract Apolipoprotein B (apo B) messenger RNA (mRNA)‐editing, catalytic polypeptide (APOBEC) cytidine deaminases (CDAs), which can insert mutations into DNA and/or RNA as a result of their ability to deaminate cytidine (C) to uridine (U), originated from a branch of the zinc‐dependent deaminase superfamily at the beginning of vertebrate radiation. The ability of mammalian CDAs encoded by the APOBEC3 genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including human immunodeficiency virus‐1, is well established. Furthermore, APOBEC1 from a variety of mammalian species, which mediates the C‐to‐U deamination of apo B mRNA, a protein involved in lipid transport, also has a role in controlling mobile elements. A large portion of the mammalian genome is derived from ancient transposable elements. Retroelements, transported by an intracellular copy‐and‐paste process involving an RNA intermediate, constitute the majority of these mobile genetic elements. Endogenous retroviruses are long‐terminal repeat (LTR)‐type retroelements that account for approximately 10% of human and murine genomic DNA. Non‐LTR members are present in extremely high copy numbers, with approximately 40% of the human and murine genomes consisting of long‐interspersed nuclear element‐1 (L1). These L1 elements modify mammalian genomes not only through insertions but also by the indirect replication of non‐autonomous retrotransposons. As expected, vertebrate intrinsic immunity has evolved to support a balance between retroelement insertions that cause deleterious gene disruptions and those that confer beneficial genetic diversity. This review discusses the current understanding of the mechanism of action of APOBEC CDAs and their role in controlling retroviruses and retroelements. WIREs RNA 2012, 3:529–541. doi: 10.1002/wrna.1117 This article is categorized under: RNA Processing > RNA Editing and Modification

Activation‐induced deaminase (AID)/apolipoprotein B (apo B) messenger RNA (mRNA)‐editing, catalytic polypeptide (APOBEC) genes in human and murine genomes. A schematic of the human and murine genomes containing members of the AID/APOBEC family. There are several forms of mammalian AID/APOBEC proteins with distinct functions in vivo: AID, APOBEC1, APOBEC2, APOBEC3, and APOBEC4. AID and APOBEC1 are located approximately 1 Mb apart on human chromosome 12 and 30 kb apart on mouse chromosome 6. The primate‐specific cluster consists of at least seven APOBEC3‐related genes, APOBEC3A‐3H, and resides on chromosome 22q13 within approximately 150 kb. In contrast, mice retain only a single APOBEC3 gene that is located on chromosome 15e2, indicating a relatively recent and possibly unprecedented gene expansion has occurred in mammalian species. This rapid evolution of the APOBEC3 locus is likely to be the result of selective pressure on the APOBEC3 proteins from their targets, i.e., retroviruses and retroelements. Each APOBEC3 gene encodes a protein with one or two conserved zinc‐coordinating motifs (Z1, Z2, and Z3).10,11 Green and orange denote the Z1 and Z2 domains, respectively, whereas blue denotes a Z3 domain. Rodents encode only one APOBEC3 gene (a Z2–Z3 fusion).

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Models for the retroelement retrotransposition cycle. (a) The retrotransposition pathway of endogenous retroviruses [or long‐terminal repeat (LTR)‐type retrotransposons], e.g., murine intracisternal A particle (IAP), MusD, and yeast Ty1. These LTR‐type retroelement sequences are structurally similar to mammalian infectious retroviruses. Infectious retroviruses, such as murine leukemia virus (MLV) and human immunodeficiency virus‐1 (HIV‐1), encode an envelope protein (Env) that facilitates their transmission from one cell to another, whereas endogenous retroviruses either lack or contain a remnant of an env gene and can integrate into the genome at a new site within their cell of origin. Endogenous retroviruses also contain slightly overlapping open‐reading frames (ORFs) for their group‐specific antigen (Gag), protease (Prt), polymerase (Pol), and terminal LTRs. The pol genes encode a reverse transcriptase, ribonuclease H, and integrase to generate proviral complementary DNA (cDNA) from viral genomic RNA and to insert it into the host genome. Their life cycle includes the formation of virus‐like particles that remain intracellular. Reverse transcription of retrovirus genomic RNA occurs in the cytoplasm, and is a complicated, multistep process. (b) Retrotransposition pathway of long‐interspersed nuclear element‐1 (L1) retroelements. An approximately 6 kb functional L1 element contains an internal RNA polymerase II promoter in its 5′ untranslated region (UTR), followed by two ORFs. ORF1 encodes an RNA‐binding protein (ORF1p) that is required for ribonucleoprotein particle (RNP) formation in the cytoplasm. ORF2 encodes a protein with endonuclease and reverse transcriptase activity (ORF2p). ORF1p and ORF2p are critical for retrotransposition by a ‘copy‐and‐paste’ mechanism. A short 3′‐UTR is followed by a poly(A) tail, and the entire element is flanked by target site duplications. L1 DNA synthesis in the nucleus is based on ‘target‐primed reverse transcription’ in which ORF2p nicks the target chromosomal DNA, and then uses the resultant 3′‐OH to prime the reverse transcription of L1 RNA as a template. During an early phase of replication, L1 RNA forms a RNP complex in the cytoplasm as a retrotransposition intermediate by associating with ORF1p and ORF2p. Human apolipoprotein B (apo B) messenger RNA (mRNA)‐editing, catalytic polypeptide 3 (APOBEC3) proteins have been documented to associate with stress granules, Staufen granules, or P bodies (gray enclosure); however, it appears that the inhibitory activity of human APOBEC3 proteins against L1 retrotransposition does not correlate with P‐body association.

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Model for the apolipoprotein B (apo B) messenger RNA (mRNA)‐editing enzyme complex. The catalytic subunit of apo B mRNA‐editing, catalytic polypeptide 1 (APOBEC1) deaminates cytidine 6666 of apo B mRNA. APOBEC1 requires RNA‐binding auxiliary protein (APOBEC1 complementation factor—ACF) that bind to APOBEC1 C‐terminal dimer and single‐stranded RNA molecules to provide specificity. The mooring sequence is an 11‐nucleotide sequence to which ACF bind as a dimer, while the efficiency sequence is a segment of RNA that is upstream from the editing site that increases the editing efficiency. (Reprinted with permission from Ref 5. Copyright 2003 Elsevier Limited. Reprinted with permission from Ref 13. Copyright 2011 Elsevier)

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