FANCD2 is required for the repression of germline transposable elements.

The Fanconi anemia (FA) DNA damage response (DDR) pathway regulate important cellular processes such as DNA replication, cell cycle control and DNA damage repair. Here we show that FANCD2, a key member of the FA DDR pathway, interacts with several important components of the germ-cell-specific Prmt5/piRNA pathways that orchestrate the repression of transposable elements (TEs). By using the -eGFP reporter mice, which marks pure populations of primordial germ cells (PGCs), we demonstrate that FA deficiency results in de-repression of TEs, depletion of PGCs, and defective spermatogenesis and oogenesis. PGCs exhibited excessive DNA damage and exacerbated apoptosis. Mechanistically, we observed a significant reduction of PRMT5-catalyzed H2A/H4R3me2s marks on the LINE1 TEs in E10.5 PGCs of ; -eGFP and -eGFP embryos. Furthermore, we utilized the model to show that Fancd2 and Prmt5 co-occupied the promoter of LINE1 in WT PGCs, and that this co-occupancy was lost in FA-deficient () PGCs. These results suggest that the FA pathway takes part in TE repression in early PGCs, likely through a mechanism involving Fancd2-facilitated, Prmt5-catalyzed repressive H2A/H4R3me2s marks on TEs.