1. Central Laboratory, Shenzhen Samii Medical Center, Shenzhen, Guangdong 518118, P.R. China.
2. The Department of Gynecology, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, P.R. China.
3. The Central Laboratory, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, P.R. China.
4. The Department of Gynecology & Obstetrics, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China.
5. Department of Physiology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China.
6. Department of Reproductive Medicine, The First Affiliated hospital of Jinan University, Guang zhou, Guangdong, China, 510000.
#These authors contributed equally to this study.
Adenosine (A)-to-inosine (I) RNA editing is the most prevalent RNA editing mechanism, in which adenosine deaminase acting on RNA 1 (ADAR1) is a major adenosine deaminase. Increasing evidence suggests that editing dysregulation of ADAR1 plays an important role in human tumorigenesis, while the underlying mechanism remains elusive. Here, we demonstrated that ADAR1 was highly expressed in ovarian cancer tissues and negatively correlated with progression free survival of ovarian cancer patients. Importantly, silence of ADAR1 repressed ovarian cancer cell growth and colony formation in vitro and inhibited ovarian cancer cell tumorigenesis in vivo. Further cell cycle and transcriptome profile analysis revealed that silence of ADAR1 in ovarian cancer cells induced cell cycle arrest at G1/G0 stage. Mechanistically, loss of ADAR1 caused R-loop abnormal accumulation, thereby contributing to single stand DNA break and ATR pathway activation. Additionally, ADAR1 interacted with DHX9 to regulate R-loop complex formation, and A-to-I editing of nascent RNA repressed R-loop formation during co-transcriptional process. Together, our results identify a novel ADAR1/R-loop/ATR axis critical for ovarian cancer progression and a potential target for ovarian cancer therapy.
Keywords: Ovarian Cancer, ADAR1, DNA Damage, R-Loop