UBE2T resolves transcription-replication conflicts and protects common fragile sites in primordial germ cells

The proper development of primordial germ cells (PGCs) is an essential prerequisite for gametogenesis and mammalian fertility. The Fanconi anemia (FA) pathway functions in maintaining the development of PGCs. FANCT/UBE2T serves as an E2 ubiquitin-conjugating enzyme that ubiquitylates the FANCD2-FANCI complex to activate the FA pathway, but its role in the development of PGCs is not clear. In this study, we found that Ube2t knockout mice showed defects in PGC proliferation, leading to severe loss of germ cells after birth. Deletion of UBE2T exacerbated DNA damage and triggered the activation of the p53 pathway. We further demonstrated that UBE2T counteracted transcription-replication conflicts by resolving R-loops and stabilizing replication forks, and also protected common fragile sites by resolving R-loops in large genes and promoting mitotic DNA synthesis to maintain the genome stability of PGCs. Overall, these results provide new insights into the function and regulatory mechanisms of the FA pathway ensuring normal development of PGCs.

Automated summary

In this study, Ube2t knockout mice showed defects in the proliferation of primordial germ cells (PGCs), resulting in severe loss of germ cells after birth. Deletion of UBE2T exacerbated DNA damage and activated the p53 pathway. The study also revealed that UBE2T resolves transcription-replication conflicts, protects common fragile sites, and promotes mitotic DNA synthesis to maintain the genomic stability of PGCs. Overall, these findings provide new insights into the function and regulatory mechanisms of the Fanconi anemia pathway in ensuring the normal development of PGCs.