Lost in translation

Abstract

“Young” APE-type non-LTR retrotransposons (non-LTRs) typically encode two open reading frames (ORFs 1 and 2). The shorter ORF1 translation product (ORF1p) comprises an RNA binding activity, thought to bind to non-LTR transcript RNA, protect against nuclease degradation and specify nuclear import of the ribonuclear protein complex (RNP). ORF2 encodes a multifunctional protein (ORF2p) comprising apurinic/apyrimidinic endonuclease (APE) and reverse-transcriptase (RT) activities, responsible for genome replication and re-integration into chromosomal DNA. However, some clades of APE-type non-LTRs only encode a single ORF—corresponding to the multifunctional ORF2p outlined above (and for simplicity referred-to as ORF2 below). The absence of an ORF1 correlates with the acquisition of a 2A oligopeptide translational recoding element (some 18–30 amino acids) into the N-terminal region of ORF2p. In the case of non-LTRs encoding two ORFs, the presence of ORF1 would necessarily downregulate the translation of ORF2. We argue that in the absence of an ORF1, 2A could provide the corresponding translational downregulation of ORF2. While multiple molecules of ORF1p are required to decorate the non-LTR transcript RNA in the cytoplasm, conceivably only a single molecule of ORF2p is required for target-primed reverse transcription/integration in the nucleus. Why would the translation of ORF2 need to be controlled by such mechanisms? An “excess” of ORF2p could result in disadvantageous levels of genome instability by, for example, enhancing short, interspersed, element (SINE) retrotransposition and the generation of processed pseudogenes. If so, the acquisition of mechanisms—such as 2A—to control ORF2p biogenesis would be advantageous.

LINE-1 protein localization and functional dynamics during the cell cycle

“…This hypothesis will need to be better explored in future studies, by examining ORF2p and L1 mRNA dynamics during the cell cycle. The lack of a sensitive Ab against ORF2p, the fact that most cells expressing ORF1p do not express ORF2p due to an unknown post-transcriptional mechanism controlling ORF2p expression ( Taylor et al, 2013 ; Alisch et al, 2006 ; Luke et al, 2013 ) and the difficulties of detecting ORF2p even in the context of overexpression ( Doucet et al, 2016 ), continue to technically challenge the study of L1 cellular dynamics.…”

Extracellular vesicles mediate the horizontal transfer of an active LINE‐1 retrotransposon

“…While L1‐ORF1p is an RNA binding protein with chaperone activity, L1‐ORF2p contains domains with endonuclease and reverse transcriptase activity. Multiple molecules of L1‐ORF1p are required to form the RNP complex in the cytoplasm, whereas only a single molecule of L1‐ORF2p is required for TPRT in the nucleus [47–50]. Previous studies have showed the importance of expression of L1‐encoded ORF1 and ORF2, particularly the endonuclease and reverse transcriptase activity of ORF2p, in effective retrotransposition.…”

RNA Viruses: RNA Roles in Pathogenesis, Coreplication and Viral Load

“…ORF2 encodes a multifunctional protein (ORF2p) comprising apurinic/apyrimidinic endonuclease (APE) and reverse-transcriptase (RT) activities, responsible for retroelement’s replication and their integration into chromosomal DNA. However, some clades of APE-type retroelements only encode a single ORF-corresponding to the multifunctional ORF2p [ 4 ]. HERVs, closely resembling infectious retroviruses, have mutated and/or truncated provirus structures and have lost their ability to replicate or retrotranspose.…”