Li Peng, Song Licun, Ma Longfei, Han Chunsheng, Li Lejun, Lu Lin-Yu, Liu Yidan
Key Laboratory of Reproductive Genetics (Ministry of Education), Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang Key Laboratory of Maternal and Infant Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
EMBO Rep. 2025 May 28. doi: 10.1038/s44319-025-00487-5.
Undifferentiated spermatogonia, which form shortly after birth, consist of spermatogonial stem cells and progenitor spermatogonia that maintain homeostasis. As the origin of spermatogenesis, undifferentiated spermatogonia must preserve genome integrity. Paradoxically, we demonstrate that massive spontaneous DNA damage, potentially generated by formaldehyde, arises during the formation of undifferentiated spermatogonia, posing a significant threat to genome integrity. We further reveal that BRCA1 is essential for the timely repair of this spontaneous DNA damage. BRCA1 loss leads to a dramatic reduction in progenitor spermatogonia and disrupts the formation of undifferentiated spermatogonia. Although spermatogonial stem cells initially undergo hyperproliferation, they are eventually depleted, resulting in the premature exhaustion of undifferentiated spermatogonia. Our study highlights a striking difference in DNA damage sensitivity between the two populations of undifferentiated spermatogonia and underscores the critical role of BRCA1-dependent DNA damage repair in preserving genome integrity during the formation of undifferentiated spermatogonia.
出生后不久形成的未分化精原细胞由维持内环境稳定的精原干细胞和祖代精原细胞组成。作为精子发生的起源，未分化精原细胞必须保持基因组完整性。矛盾的是，我们证明在未分化精原细胞形成过程中会出现大量可能由甲醛产生的自发性DNA损伤，这对基因组完整性构成了重大威胁。我们进一步揭示，BRCA1对于及时修复这种自发性DNA损伤至关重要。BRCA1的缺失导致祖代精原细胞显著减少，并破坏未分化精原细胞的形成。尽管精原干细胞最初会经历过度增殖，但最终会耗尽，导致未分化精原细胞过早耗竭。我们的研究突出了两种未分化精原细胞群体在DNA损伤敏感性上的显著差异，并强调了BRCA1依赖性DNA损伤修复在未分化精原细胞形成过程中保持基因组完整性的关键作用。
