BRCA1 preserves genome integrity during the formation of undifferentiated spermatogonia

Abstract 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.