SIAH1 Promotes Granulosa Cells Senescence and Contributes to Premature Ovarian Failure by Reducing the Stability of TRF2

Background: Reactive oxygen species (ROS) exposure is an important trigger for granulosa cell (GC) senescence, which is considered to be an important cause of premature ovarian failure (POF). However, the cellular mechanisms that mediate this process needs further exploration. Methods: We respectively detected the ROS level and senescence level in the ovarian tissues and granulosa cells in POF rats. We also treated granular cells with H2O2  and antioxidant N-acetylcysteine (NAC) to detect the level of ROS and downstream protein levels, as well as the level of cell senescence. Findings: In the present, we observed that ROS levels were increased in the ovarian tissues of POF models in vivo, follicular GCs of POF patients and cyclophosphamide (CTX) pretreated GCs. In addition, ROS induced by H2O2 treatment was shown to significantly increase in SIAH1 expression, TRF2 reduction and senescence in GCs, which could be diminished by treatment with the Antioxidant N-acetylcysteine (NAC) or SIAH1 downregulation. Moreover, TRF2 was co-localized with SIAH1 in the cytoplasm, and SIAH1 was able to facilitate the ubiquitination and degradation of TRF2 via the ubiquitin-proteasome pathway, further leading to abnormalities in the telomeres of GCs. Interpretation: Our results indicate that ROS induces telomere abnormalities in GCs by promoting SIAH1-mediated TRF2 degradation, which causes cellular senescence, and finally contributes to POF. Funding Statement: This research was supported by the Natural Science Foundation of China (grant no. 81672913/81871343), the Social Development Project of Jiangsu (grant no. BE2018693/BE2017698), Natural Science Foundation of Jiangsu Province (grant no. BK20181226), the Jiangsu Provincial Medical Youth Talent (QNRC2016460, FRC201788) Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the Reproductive Medical Center of the Fourth Affiliated Hospital of Jiangsu University, and the research protocol was approved by Jiangsu University Ethics Committee.