A Cytoplasmic Self-Priming Retrotransposon

Article: Human Cells Can Synthesize DNA in Their Cytoplasm
Source: The Scientist
Published: February 8, 2021

This news article by The Scientist is a follow up to articles about Jayakrishna Ambati's research into NRTIs as a potential therapeutic for atrophic AMD. The article approaches the research with a focus on cytoplasmic DNA. This finding in itself is novel to basic science. In particular, Alu is an endogenous retrotransposon found in the human genome, but its presence and reverse transcription in the cytoplasm rather than in the nucleus of cells was unexpected. After all, most DNA synthesis requires the transcription "equipment," such as a primer, normally located in the cell's nucleus. After investigating the sequence and RNA structure of Alu, Ambati's latest study (part of a decade of research into this topic) found that this retrotransposon could undergo self-priming. If the presence of Alu elements in the cytoplasm wasn't surprising enough, the fact that Alu is self-priming was an additional novel finding given that there is only one other RNA molecule, from a rodent gene, shown to self-prime; however, the other gene is not found in the cytoplasm. Alu is the first retrotrotransposon known to initiate its own reverse transcription, and does so in the cell's cytoplasm. Unfortunately, the fact that this retrotransposon exists in the cytoplasm is related to a disease state, triggering inflammation that eventually leads to many age-related diseases, such as macular degeneration in this case. Nucleoside reverse transcriptase inhibitors (NRTIs), drugs FDA approved for the treatment of HIV, were discussed previously for their potential to be repurposed for the treatment of diseases due to the inflammasome. In earlier research, Ambati's team showed that NRTIs have an anti-inflammatory effect. In the most recent study, the researchers showed that NRTIs have an additional effect of inhibiting transcription of cytoplasmic Alu.

Personal commentary: The Scientist news team featured commentary by a geneticist from Johns Hopkins University, who is also studying retrotransposons. He comments that the evidence looks pretty good. The article also provided a more nuanced detail that Ambati's study analyzed nearly 35 million patient records in four insurance databases comprising over 100 million Americans.

My rating of this article: ⭐⭐⭐

Fukuda S, Varshney A, Fowler BJ, et al. "Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration." PNAS. 118(6):e2022751118. 9 February 2021. https://doi.org/10.1073/pnas.2022751118