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Background <p>Adenosine deaminase acting on RNA (Adar) is a critical enzyme involved in post-transcriptional epigenetic regulation through adenosine-to-inosine (A-to-I) RNA editing. However, the biological role and regulatory mechanisms of Adar remain largely unknown.</p> Results <p>Using <i>Drosophila</i> as a model, we found that loss of Adar leads to spontaneous genome instability characterized by DNA damage and mitotic defects. Genome-wide ssDRIP-seq revealed global R-loop accumulation in Adar mutants, particularly at gene promoters, introns, and repetitive regions including telomeric retrotransposons. Notably, overexpression of RNase H1 (RNH1) suppressed R-loop accumulation and rescued genome instability in Adar-deficient flies. Strikingly, a catalytically inactive Adar mutant (E374A), which lacks A-to-I editing activity, retained its ability to suppress R-loop accumulation and preserve genome integrity.</p> Conclusions <p>Our findings identify a novel editing-independent role of Adar in maintaining genome stability via regulation of R-loop homeostasis. This work highlights the evolutionarily conserved functions of Adar beyond RNA editing and establishes <i>Drosophila</i> as a valuable model to study R-loop-mediated genomic instability.</p>

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Adar contributes to genome integrity by regulating R-loop homeostasis in Drosophila

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月15日

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  • Xuedi Zhang,
  • Hongyun Liu,
  • Ju Peng,
  • Guangbin Wang,
  • Xiangyu Wu,
  • Shuai Li,
  • Jie Zheng,
  • Qianwen Sun,
  • Guanjun Gao

摘要

Background

Adenosine deaminase acting on RNA (Adar) is a critical enzyme involved in post-transcriptional epigenetic regulation through adenosine-to-inosine (A-to-I) RNA editing. However, the biological role and regulatory mechanisms of Adar remain largely unknown.

Results

Using Drosophila as a model, we found that loss of Adar leads to spontaneous genome instability characterized by DNA damage and mitotic defects. Genome-wide ssDRIP-seq revealed global R-loop accumulation in Adar mutants, particularly at gene promoters, introns, and repetitive regions including telomeric retrotransposons. Notably, overexpression of RNase H1 (RNH1) suppressed R-loop accumulation and rescued genome instability in Adar-deficient flies. Strikingly, a catalytically inactive Adar mutant (E374A), which lacks A-to-I editing activity, retained its ability to suppress R-loop accumulation and preserve genome integrity.

Conclusions

Our findings identify a novel editing-independent role of Adar in maintaining genome stability via regulation of R-loop homeostasis. This work highlights the evolutionarily conserved functions of Adar beyond RNA editing and establishes Drosophila as a valuable model to study R-loop-mediated genomic instability.