Figure 2

Modulators of the L1 lifecycle. The L1 amplification cycle can be divided into several steps. (a) Transcription. L1 amplification initiates with transcription, and regulation of L1 at this step can be modified by epigenetic modifications, DNA methylation, and recruitment of transcription factors. (b) Before leaving the nucleus, the number of retrocompetent full-length L1 transcripts can be reduced by RNA processing through premature polyadenylation and splicing. (c) Translation. Full-length L1 enters the cytoplasm to be translated, producing ORF1 and ORF2 proteins for retrotransposition. The two proteins interact with the L1 transcript to form an L1 ribonucleoprotein particle (RNP). RNA interference can affect this step. (d) Insertion of a new L1 copy. The L1 RNP reaches the nucleus, where the DNA is cleaved by the L1 ORF2 endonuclease activity. It is proposed that reverse transcription occurs through a process referred to as target primed reverse transcription (TPRT) [71]. The L1 ORF2 reverse transcriptase activity generates the first strand of DNA. DNA repair proteins are likely to be involved in inhibiting the L1 integration step. (e) Effects of external stimuli. Ionizing radiation or heavy metals can affect L1 at multiple steps, such as transcriptional activation or altering DNA repair pathways.