Abstract
Endogenous retroviruses (ERVs) in mammals are closely related to infectious retroviruses and utilize host tRNAs as a primer for reverse transcription and replication, a hallmark of long terminal repeat (LTR) retroelements. Their dependency on tRNA makes these elements vulnerable to targeting by small RNAs derived from the 3′-end of mature tRNAs (3′-tRFs), which are highly expressed during epigenetic reprogramming and potentially protect many tissues in eukaryotes. Here, we review some key functions of ERV reprogramming during mouse and human development and discuss how small RNA-mediated silencing maintains genome stability when ERVs are temporarily released from heterochromatin repression. In particular, we take a closer look at the tRNA primer binding sites (PBS) of two highly active ERV families in mice and their sequence variation that is shaped by the conflict of successful tRNA priming for replication versus evasion of silencing by 3′-tRFs.
Highlights
Reverse transcription and long terminal repeat (LTR) retroelements are ancient components of eukaryotic genomes [1]
The majority of LTR-retrotransposons in mammals are closely related to known infectious LTR-retroviruses and are called endogenous retroviruses (ERVs)
The most famous example of an ERV-induced metastable epiallele is the differential methylation of an intracisternal A-particle (IAP) insertion upstream the mouse Agouti gene which results in varying fur color and obesity in siblings [30]
Summary
Reverse transcription and long terminal repeat (LTR) retroelements are ancient components of eukaryotic genomes [1]. Small RNAs derived from the 30 -end of tRNAs (30 -tRFs) target LTR-retroelements at the PBS and control their mobility and expression [22,23,24] These highly conserved sequence motifs are a prerequisite for replication and allow host defense mechanisms to identify active LTR-retroelements. The 30 -end of cellular tRNAs (blue cloverleaf) primes reverse transcription by hybridizing to the primer binding site (PBS) While this segment is being copied into first-strand cDNA (light blue line), called minus (−) strong stop DNA, the RNaseH activity of reverse transcriptase (RT) degrades the template RNA. In Retroviridae, the plus strand PBS is a copy of the tRNA primer, while the minus strand is a copy of the original PBS sequence After another transfer event, first (−) and second (+) strand synthesis are completed to result in a full-length, double-stranded retroviral DNA that will be integrated into the host genome
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