Studies On The Modulation Of APOBEC3 On LINE-1 And SVA Retrotransposition

Retrotransposon LINE-1 is a kind of retroelement that can be autonomous mobile in the genome.More about 34% of the human genome resulted from LINE-1 extensive proliferation.It has been confirmed that the LINE-1-encoded endonuclease can elicit double-strand breaks that may lead to genomic instability.Besides,LINE-1 retrotransposition in the genome can lead to single-gene diseases.Mammalian cells have evolved a series of defense mechanism to regulate mobility and reduce deleterious consequences caused by the transposition.The human cytidine deaminase family APOBEC3 proteins,a kind of emerging family proteins,represent an essential role in the field of intracellular defense against retroelements.It has been shown that APOBEC3 members inhibit LINE-1 retrotransposition by 35%–99%.However,genomic LINE-1 retrotransposition events that modulated by APOBEC3 proteins,outside of A3 A,lack of detectable G-to-A hypermutations,suggesting that one or multiple deaminase-independent LINE-1 restricting mechanisms.Herein,we identified that APOBEC3 proteins are a family group of inhibitor of LINE-1 in varying degrees.But it should to be noted that this kind of inhibitory effect could not simply be explained by the interactions between A3 and the LINE-1 ORF1 p or their co-localization.Using a sophisticated LINE-1 element amplification protocol(LEAP),we demonstrated that human A3 proteins could target on LINE-1 RNP complex selectively and inhibite LINE-1 ORF2 p reverse transcriptase activity.Moreover we found that A3 B,A3DE and A3H_HapII regulate LINE-1 retrotransposition in a CDD or RNA-binding pocket domain independent manner.This indicates that APOBEC3 proteins use different mechanisms against retrovirus HIV-1 and retrotransposon LINE-1.In this study,we confirmed that APOBEC3 family protein is an inhibiting factor against another kind of nonautonomy retrotransposon SVA.APOBEC3 G potently restrict SVA retrotransposion but fail to inhibit LINE-1.It suggested that APOBEC3 family proteins modulate LINE-1 and SVA retrotransposition through distinct mechanisms.Meanwhile,we demonstrated that the APOBEC3 H unstable haplotypes have the function of suppressing SVA.It implys that the selective evolution of human apobec3 H gene that the control of certain retroelement(s)was conserved.In conclusion,this study demonstrates the regulation effect of APOBEC3 family proteins on retrotransposon LINE-1 and SVA;APOBEC3 use different mechanisms on inhibiting HIV-1 and LINE-1;APOBEC3H haplotypes unstable proteins have certain functions on SVA restriction.This study provides more evidences for APOBEC3 proteins as a broad spectrum antiviral factor.