APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses

Abstract

Endogenous retroviruses are multicopy retroelements accounting for nearly 10% of murine or human genomes. These retroelements spread into our ancestral genome millions of years ago and have acted as a driving force for genome evolution. Endogenous retroviruses may also be deleterious for their host, and have been implicated in cancers and autoimmune diseases. Most retroelements have lost replication competence because of the accumulation of inactivating mutations, but several, including some murine intracisternal A-particle (IAP) and MusD sequences, are still mobile. These elements encode a reverse transcriptase activity and move by retrotransposition, an intracellular copy-and-paste process involving an RNA intermediate. The host has developed mechanisms to silence their expression, mainly cosuppression and gene methylation. Here we identify another level of antiviral control, mediated by APOBEC3G, a member of the cytidine deaminase family that was previously shown to block HIV replication. We show that APOBEC3G markedly inhibits retrotransposition of IAP and MusD elements, and induces G-to-A hypermutations in their DNA copies. APOBEC3G, by editing viral genetic material, provides an ancestral wide cellular defence against endogenous and exogenous invaders.

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

“…Investigation of the sequences surrounding the edited nucleotides revealed dominance of adenosines at position + 2 relative to the editing site (GxA→AxA motif; the underlined G is the editing site; Methods and Supplementary Table S1). This is in agreement with previous experimental studies [14][15][16][17][18][19][20]23,24 and supports the identification of these mismatches as an outcome of mouse APOBEC3 activity.…”

“…The mouse retrotransposons intracisternal A-particle (IAP) and early transposon (ETn/MusD) were edited when transfected into HeLa cells together with APOBEC3G 16 , and some of their genomic elements were found to be edited relative to their consensus 16 . We scanned the pairwise alignments of the entire IAP family for stretches of at least 12 consecutive G-to-A mismatches that occurred by chance with probability at most 10 − 12 , based on the frequency of the other transition mutations (Methods).…”

“…This process is thus called DNA editing. In recent years, it was shown that active LTR (long terminal repeat) retrotransposons, which are endogenous retroviruses, can also be edited [14][15][16][17][18][19][20][21] . However, the impact of DNA editing on genome variability has not been explored to date 22 .…”

Reconstructing immune phylogeny: new perspectives

“…So, the appearance of a class-switch reaction was dependent on the evolution of switch-region sequences. AID-like and uracil-DNA glycosylase (UNG)-like proteins, which are involved in these processes, had ancient origins, co-evolving with innate immune antiviral defences [49][50][51] .…”

“…So, the appearance of a class-switch reaction was dependent on the evolution of switch-region sequences. AID-like and uracil-DNA glycosylase (UNG)-like proteins, which are involved in these processes, had ancient origins, co-evolving with innate immune antiviral defences [49][50][51] .Over time, V-gene duplication and germline substitutions, which were focused in COMPLEMENTARITY-DETERMINING REGION 1 (CDR1) and CDR2, coupled with combinatorial joining, imparted a considerable selective advantage in terms of deriving receptor diversity. Somatic hypermutation of immunoglobulin genes, which is a central feature of BCR maturation, occurs in the earliest extant jawed vertebrates -the cartilaginous fish 52,53 -and might be an accentuation of a genome-wide process 54,55 .…”