After fertilization and formation of the pronuclei, the mammalian zygote initiates DNA replication. This replication relies on maternal factors that are provided by the oocyte, and coincides with a reorganization of the genome, DNA demethylation and the occurrence of DNA damage. The cullin ring-finger ubiquitin ligase 4 (CRL4) has previously been shown by Heng-Yu Fan and colleagues to orchestrate several functions in oocytes and post fertilization. In this issue (p. 3297), they now address the role of the substrate receptor of CRL4, DCAF2, in oogenesis and embryogenesis. The authors specifically delete DCAF2 in mouse oocytes, which leads to female infertility. Embryos from DCAF2-knockout oocytes arrest at the one- or two-cell stage, with a strong accumulation of DNA damage. DCAF2 is required for normal DNA methylation levels at the oocyte-to-embryo transition. Furthermore, absence of DCAF2 leads to an over-replication of DNA and persistence of the DNA replication licencing factor and CRL4-target CDT1 in zygotes. Taken together, this work establishes a role for DCAF2 in the transition from the female germline to the zygote and the completion of the first mitotic cell cycle by preventing DNA re-replication and safeguarding the stability of the zygotic genome.
