期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：34
DOI：10.1073/pnas.2203208119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Germ cells are capable of preserving their genetic information with high fidelity. We report that rapidly dividing mouse primordial germ cells (PGCs) are faced with high levels of endogenous replication stress due to frequent occurrence of transcription–replication conflicts (TRCs). Thus, PGCs have an increased requirement for the replication-coupled Fanconi anemia (FA) pathway to counteract TRC-induced replication stress, enabling their rapid proliferation to establish a sufficient reproductive reserve. This work provides insights into the unique genome feature of developing PGCs and helps to explain the reproductive defects in FA individuals.
Preserving a high degree of genome integrity and stability in germ cells is of utmost importance for reproduction and species propagation. However, the regulatory mechanisms of maintaining genome stability in the developing primordial germ cells (PGCs), in which rapid proliferation is coupled with global hypertranscription, remain largely unknown. Here, we find that mouse PGCs encounter a constitutively high frequency of transcription–replication conflicts (TRCs), which lead to R-loop accumulation and impose endogenous replication stress on PGCs. We further demonstrate that the Fanconi anemia (FA) pathway is activated by TRCs and has a central role in the coordination between replication and transcription in the rapidly proliferating PGCs, as disabling the FA pathway leads to TRC and R-loop accumulation, replication fork destabilization, increased DNA damage, dramatic loss of mitotically dividing mouse PGCs, and consequent sterility of both sexes. Overall, our findings uncover the unique source and resolving mechanism of endogenous replication stress during PGC proliferation, provide a biological explanation for reproductive defects in individuals with FA, and improve our understanding of the monitoring strategies for genome stability during germ cell development.
