4.8 Article

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

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2203208119

Keywords

primordial germ cells; replication stress; transcription-replication conflicts; genome stability; Fanconi anemia pathway

Funding

  1. Basic Science Center Program of National Natural Science Foundation of China [31988101]
  2. National Key Research & Development Program of China [2021YFC2700100]
  3. National Natural Science Foundation for Distinguished Young Scholars [82125014]
  4. National Natural Science Foundation of China [81873823, 32170867, 82071609]
  5. Shandong Provincial Key Research and Development Program [2020ZLYS02]
  6. Natural Science Foundation of Shandong Province for Grand Basic Projects [ZR2021ZD33]
  7. Qilu Young Scholars Program of Shandong University
  8. Fundamental Research Funds of Shandong University
  9. Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences [2020RU001]

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This study reveals that mouse PGCs experience a high frequency of transcription-replication conflicts, leading to replication stress and DNA damage. The FA pathway is found to play a crucial role in PGC proliferation, and disabling this pathway results in severe cell loss and sterility.
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.

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