BRCA1 safeguards genome integrity by activating chromosome asynapsis checkpoint to eliminate recombination- defective oocytes

• 成果类型: Article
• 署名作者: Bai, Long; Li, Peng; Xiang, Yu; Jiao, Xiaofei; Chen, Jiyuan; Song, Licun; Liang, Zhongyang; Liu, Yidan; Zhu, Yimin; Lu, Lin- Yu
• 署名单位: Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Westlake Laboratory; Westlake University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12366
• DOI: 10.1073/pnas.2401386121
• 发表日期: 2024-05-07
• 关键词: dna-damage response; homologous recombination; meiotic recombination; SURVEILLANCE; chromatin; cells; mice

摘要

In the meiotic prophase, programmed DNA double - strand breaks are repaired by meiotic recombination. Recombination - defective meiocytes are eliminated to preserve genome integrity in gametes. BRCA1 is a critical protein in somatic homologous recombination, but studies have suggested that BRCA1 is dispensable for meiotic recombination. Here we show that BRCA1 is essential for meiotic recombination. Interestingly, BRCA1 also has a function in eliminating recombinationdefective oocytes. Brca1 knockout (KO) rescues the survival of Dmc1 KO oocytes far more efficiently than removing CHK2, a vital component of the DNA damage checkpoint in oocytes. Mechanistically, BRCA1 activates chromosome asynapsis checkpoint by promoting ATR activity at unsynapsed chromosome axes in Dmc1 KO oocytes. Moreover, Brca1 KO also rescues the survival of asynaptic Spo11 KO oocytes. Collectively, our study not only unveils an unappreciated role of chromosome asynapsis in eliminating recombinationdefective oocytes but also reveals the dual functions of BRCA1 in safeguarding oocyte genome integrity.