Transcription–replication conflicts in primordial germ cells necessitate the Fanconi anemia pathway to safeguard genome stability

• DOI: 10.1073/pnas.2203208119
• Publication Date: 2022-08-15T19:21:26Z
• Authors: Yajuan Yang; Weiwei Xu; Fei Gao; Canxin Wen; Simin Zhao; Yongze Yu; Wenlin Jiao; Xin Mi; Yingying Qin; Zi-Jiang Chen; Shidou Zhao
• Keywords: DNA re-replication; Transcription

Preserving a high degree of genome integrity and stability in germ cells is utmost importance for reproduction species propagation. However, the regulatory mechanisms maintaining developing primordial (PGCs), which rapid proliferation coupled with global hypertranscription, remain largely unknown. Here, we find that mouse PGCs encounter constitutively frequency transcription-replication conflicts (TRCs), lead to R-loop accumulation impose endogenous replication stress on PGCs. We further demonstrate Fanconi anemia (FA) pathway activated by TRCs has central role coordination between transcription rapidly proliferating PGCs, as disabling FA leads TRC accumulation, fork destabilization, increased DNA damage, dramatic loss mitotically dividing consequent sterility both sexes. Overall, our findings uncover unique source resolving mechanism during PGC proliferation, provide biological explanation reproductive defects individuals FA, improve understanding monitoring strategies cell development.