Cellular inhibitors of long interspersed element 1 and Alu retrotransposition

Abstract

Long interspersed element (LINE) 1 retrotransposons are major genomic parasites that represent Ϸ17% of the human genome. The LINE-1 ORF2 protein is also responsible for the mobility of Alu elements, which constitute a further Ϸ11% of genomic DNA. Representative members of each element class remain mobile, and deleterious retrotransposition events can induce spontaneous genetic diseases. Here, we demonstrate that APOBEC3A and APOBEC3B, two members of the APOBEC3 family of human innate antiretroviral resistance factors, can enter the nucleus, where LINE-1 and Alu reverse transcription occurs, and specifically inhibit both LINE-1 and Alu retrotransposition. These data suggest that the APOBEC3 protein family may have evolved, at least in part, to defend the integrity of the human genome against endogenous retrotransposons.APOBEC3 protein ͉ mutagenesis ͉ retrotransposon ͉ genome stability ͉ intrinsic immunity

APOBEC3 genes: retroviral restriction factors to cancer drivers

“…While A3G resides in the cytoplasm, where it becomes incorporated into retroviral virions, A3 enzymes such as A3A, A3B and A3C enter the nucleus, where they are able to target other pathogens including human papillomaviruses (HPV) and also retrotransposons; mobile elements within the genome which appear to be targeted by multiple APOBEC enzymes via a variety of mechanisms [12][13][14][15][16][17][18][19]. With nuclear localization however, comes the risk of off-target activity against host genomic DNA and the potential for mutagenesis.…”

“…The single domain A3s (A3A, C and H), at around 23kDa are able to enter the nucleus via passive diffusion, whereas the larger A3B, D, F and G require an active import mechanism [14]. A3B contains a NLS and localizes to the nuclei of transfected cells, while A3D, F and G are cytoplasmic and do not appear to come into contact with DNA, even following breakdown of the nuclear envelope during mitosis [13,14,54].…”

Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes

“…Cellular RNA editing model of viral restriction is particularly relevant for A3A, where mutations in the inhibited virus DNAs have yet to be conclusively demonstrated. 12,13,17,19,23 Nevertheless, a direct link between host gene RNA editing and antiviral function of A3A remains to be demonstrated.…”

“…22 However, DNA mutations in the infectious agents restricted by A3A could not be conclusively demonstrated. 12,13,17,19,23 In this study, we examine the impact of A3A overexpression in the human transcriptome by characterizing the transcriptome wide C > U RNA editing and gene expression changes upon exogenous expression in HEK293T cells. Our results show an unprecedented extent of RNA editing by A3A.…”

“…[12][13][14][15][16][17][18][19] The virusrestricting functions of A3A are typically demonstrated by reduced infectivity of the virus upon exogenous co-expression of the plasmids encoding the enzyme and viruses in a cell line such as HEK293T human embryonic kidney cells. [12][13][14][15][16][17]19 Although A3A's cytidine deaminase function is essential for its antiviral activities, 6,12,20,21 the mechanism by which A3A inhibits viruses is not understood well. A3A efficiently mutates single stranded DNA oligonucleotides in vitro 11 and transfected plasmid DNAs in overexpression systems.…”