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

Poltronieri, Palmiro; Sun, Binlian; Mallardo, Massimo

Long Interspersed Nuclear Elements-1 (LINE-1) and endogenous retroviruses (HERVs) encode reverse transcriptase (RT) proteins in vertebrates. LINE-1s (L1s), the most studied, active autonomous mobile DNA in humans, accounts for about 17% of human DNA while HERVs account for about 8% and, together with the non-autonomous SINE/Alu family (about 10%) constitute a large proportion of the human genome. L1s encode two open reading frames (ORFs 1 and 2). The shorter ORF1 translation product (ORF1p) is an RNA binding protein, thought to also bind to non-retroviral transcripts, protects 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 reversetranscriptase (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. Nonetheless, proteins encoded by different types of HERVs are still exerting biological activities and most of the HERV-associated regulatory regions, termed "long terminal repeats" (LTRs), preserve their functions as a promoter-enhancer region. Functional "awakening" of HERVs and LTRs from their epigenetic silencing can play causative roles in tumorigenesis; in particular, HERV-K (HML-2), the most recently integrated family with a nearly complete retroviral structure, is involved in neoplastic and autoimmune pathological processes [5] . Retroelements, which mobilize throughout the genomes by a copy-and-paste process involving RNA intermediates, have the potential to modify mammalian genomes not only through insertional mutagenesis yet generating many other novelties that alter genomes both structurally and functionally [6] . Not surprisingly, cells have adopted strategies aiming at restricting the mobility and deleterious consequences of uncontrolled retrotransposition [6] .