# Biogenesis and function of retrotransposon-derived circular DNA

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $451,910

## Abstract

ABSTRACT
Retrotransposons are highly enriched in animal genome. Their activation can rewrite the host genetic information
and fundamentally impact host biology. While developmental activation of retrotransposons can bring hosts
benefits, such as against virus infection, uncontrolled activation promotes diseases or potentially drives aging.
Despite their abundance and fundamental impacts on host physiology and pathology, the study of
retrotransposons remains an underexplored area of biomedical research. Using new tools and biological systems
developed by my team, in the long-term, we aim to characterize the retrotransposon replication cycle and explore
the impact of their activation to the hosts under physiological and pathological conditions.
Upon activation, retrotransposons use their mRNA as templates to synthesize double-stranded DNA for making
new insertions in the host genome. While the reverse transcriptase encoded by them can synthesize the 1st-
strand DNA, how the 2nd-strand DNA is generated remains largely unknown. Our recent studies on both
Drosophila and mouse retrotransposons indicated that they hijack the alternative end-joining (alt-EJ) DNA repair
process from the hosts for a circularization step to synthesize their 2nd-strand DNA. Strikingly, we found that only
10% of replicated retrotransposon DNA achieve new insertions, while 90% exist as extrachromosomal circular
DNA (eccDNA). These results lead us to propose that alt-EJ plays a conserved function for retrotransposon DNA
replication by driving a circularization step, and that this step dominantly manufactures retrotransposon eccDNA
to impact on host biology. To test these hypotheses, we aim to characterize how alt-EJ mediates the
circularization step for retrotransposon DNA replication (Aim 1), to investigate how retrotransposon eccDNA can
generate genomic variation by integrating into the host genome (Aim 2), and to explore whether human
retrotransposons also hijack alt-EJ pathway for eccDNA biogenesis (Aim 3).
Collectively, our proposed research will broadly impact the field by identifying new mechanisms to understand
the replication process of the most abundant genomic elements. Meanwhile, our work will elucidate how
retrotransposon eccDNA could impact host genome by creating genomic variations. As such, our work will
provide a new perspective to understand the process and consequence of retrotransposon life cycle.

## Key facts

- **NIH application ID:** 10772281
- **Project number:** 1R01GM152423-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Zhao Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $451,910
- **Award type:** 1
- **Project period:** 2024-07-17 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772281

## Citation

> US National Institutes of Health, RePORTER application 10772281, Biogenesis and function of retrotransposon-derived circular DNA (1R01GM152423-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10772281. Licensed CC0.

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