lncRNA DDGC participates in premature ovarian insufficiency through regulating RAD51 and WT1

Duan Li; Weiwei Xu; Xiaoyan Wang; Yujie Dang; Lan Xu; Gang Lu; Wai-Yee Chan; Peter C K Leung; Shidou Zhao; Yingying Qin

doi:10.1016/j.omtn.2021.10.015

lncRNA DDGC participates in premature ovarian insufficiency through regulating RAD51 and WT1

Mol Ther Nucleic Acids. 2021 Oct 20:26:1092-1106. doi: 10.1016/j.omtn.2021.10.015. eCollection 2021 Dec 3.

Authors

Duan Li^{1

2

3

4

5}, Weiwei Xu^{1

2

3

4

5}, Xiaoyan Wang^{1

2

3

4

5}, Yujie Dang^{1

2

3

4

5}, Lan Xu^{1

2

3

4

5}, Gang Lu⁶, Wai-Yee Chan⁶, Peter C K Leung⁷, Shidou Zhao^{1

2

3

4

5}, Yingying Qin^{1

2

3

4

5}

Affiliations

¹ Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
² Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong 250012, China.
³ Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China.
⁴ Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong 250012, China.
⁵ National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China.
⁶ CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, the Chinese University of Hong Kong, Hong Kong, China.
⁷ Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.

Abstract

The list of long non-coding RNAs (lncRNAs) that participate in the function of ovarian granulosa cells (GCs) is rapidly expanding, but the mechanisms through which lncRNAs regulate GC function are not yet fully understood. Here, we recognized a minimally expressed lncRNA RP4-545C24.1 (which we named DDGC) in GCs from patients with biochemical premature ovarian insufficiency (bPOI). We further explored the role of lncRNA DDGC in GC function and its contribution to the development of bPOI. Mechanistically, silencing DDGC downregulated RAD51 by competitively binding with miR-589-5p, and this resulted in significant inhibition of DNA damage repair capacity. In addition, decreased expression of DDGC promoted ubiquitin-mediated degradation of Wilms tumor 1 (WT1) protein through interactions with heat shock protein 90 (HSP90), which led to aberrant differentiation of GCs. Moreover, DDGC was able to ameliorate the etoposide-induced DNA damage and apoptosis in vivo. Taken together, these findings provide new insights into the contribution of lncRNAs in POI pathogenesis.

Keywords: RAD51; WT1; granulosa cells; lncRNA; premature ovarian insufficiency.