2. Academic Validation
  3. Dynamic R-loops at centromeres ensure chromosome alignment during oocyte meiotic divisions in mice

Dynamic R-loops at centromeres ensure chromosome alignment during oocyte meiotic divisions in mice

  • Sci Bull (Beijing). 2025 Feb 13:S2095-9273(25)00168-9. doi: 10.1016/j.scib.2025.02.009.
Yinghong Chen 1,  Liying Wang 2,  Qiuxing Zhou 3,  Wei Wei 3,  Huafang Wei 2,  Yanjie Ma 1,  Tingting Han 3,  Shuang Ma 4,  Xiaoming Huang 3,  Meijia Zhang 5,  Fei Gao 6,  Chao Liu 7,  Wei Li 8
Affiliations

Affiliations

  • 1 Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China.
  • 3 Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
  • 4 Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
  • 5 The Innovation Centre of Ministry of Education for Development and Diseases, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China. Electronic address: zhangmeijia@scut.edu.cn.
  • 6 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: gaof@ioz.ac.cn.
  • 7 Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: liuchao@gwcmc.org.
  • 8 Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: leways@gwcmc.org.
PMID: 39984387 DOI: 10.1016/j.scib.2025.02.009
Abstract

R-loops play various roles in many physiological processes, however, their role in meiotic division remains largely unknown. Here we show that R-loops and their regulator RNase H1 are present at centromeres during oocyte meiotic divisions. Proper centromeric R-loops are essential to ensure chromosome alignment in oocytes during metaphase I (MI). Remarkably, both Rnaseh1 knockout and overexpression in oocytes lead to severe spindle assembly defects and chromosome misalignment due to dysregulation of R-loops at centromeres. Furthermore, we find that replication protein A (RPA) is recruited to centromeric R-loops, facilitating the deposition of ataxia telangiectasia-mutated and Rad3-related (ATR) kinase at centromeres by interacting with the ATR-interaction protein (ATRIP). The ATR kinase deposition triggers the activity of Chk1, stimulating the phosphorylation of Aurora B to finally promote proper spindle assembly and chromosome alignment at the equatorial plate. Most importantly, the application of ATR, Chk1, and Aurora B inhibitors could efficiently rescue the defects in spindle assembly and chromosome alignment due to RNase H1 deficiency in oocytes. Overall, our findings uncover a critical role of R-loops during mouse oocyte meiotic divisions, suggesting that dysregulation of R-loops may be associated with female infertility. Additionally, ATR, Chk1, and Aurora B inhibitors may potentially be used to treat some infertile patients.

Keywords

Centromeres; Oocyte meiotic divisions; R-loops; RNase H1.

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